COV2-pos-Drug

[{"id":330,"details":{"paperId":"7d3146f9c19827900487cb15f4dfc63b7556e409","externalIds":{"PubMedCentral":"8113585","DOI":"10.1038/s41467-021-23036-9","CorpusId":"234472535","PubMed":"33976229"},"title":"A SARS-CoV-2 antibody curbs viral nucleocapsid protein-induced complement hyperactivation","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"The crystal structure of the N protein RNA binding domain with a mAb derived from a convalescent patient is provided and it is shown that it compromises the Nprotein-induced complement hyperactivation."}},"tag":"DRUG"},{"id":79,"details":{"paperId":"7a6ba0d8e5e523b3d64b01436132f963de0a8192","externalIds":{"PubMedCentral":"8277557","DOI":"10.1016/j.bmcl.2021.128263","CorpusId":"235812842","PubMed":"34271072"},"title":"A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"A head-to-head comparison of fifteen reported peptidomimetic inhibitors in a standard FRET-based SARS-CoV-2 3CLpro inhibition assay is conducted to compare and identify potent inhibitors for development."}},"tag":"DRUG"},{"id":361,"details":{"paperId":"2c76abad8ce39e0afbe9fff6b383a8010991cc5a","externalIds":{"MAG":"3032255042","DOI":"10.1038/s41586-020-2381-y","CorpusId":"218910026","PubMed":"32454512"},"title":"A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Two monoclonal antibodies isolated from a patient with COVID-19 are shown to interfere with SARS-CoV-2–receptor binding, and one displays potent action against this virus in vitro and in a rhesus macaque model."}},"tag":"DRUG"},{"id":325,"details":{"paperId":"574c062da2bd8d08d5831cb6a27d81e8736289d5","externalIds":{"PubMedCentral":"7843602","DOI":"10.1038/s41467-021-20900-6","CorpusId":"231761648","PubMed":"33510133"},"title":"A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection, and to exhibit a synergistic antiviral effect when combined with remdesivir in vitro."}},"tag":"DRUG"},{"id":639,"details":{"paperId":"70649392a7e96838713e4abe271e9720425b3d36","externalIds":{"PubMedCentral":"8262916","DOI":"10.1128/mBio.01423-21","CorpusId":"235594694","PubMed":"34154407"},"title":"Allosteric Activation of SARS-CoV-2 RNA-Dependent RNA Polymerase by Remdesivir Triphosphate and Other Phosphorylated Nucleotides","abstract":"In vitro interrogations of the central replicative complex of SARS-CoV-2, RNA-dependent RNA polymerase (RdRp), by structural, biochemical, and biophysical methods yielded an unprecedented windfall of information that, in turn, instructs drug development and administration, genomic surveillance, and other aspects of the evolving pandemic response. They also illuminated the vast disparity in the methods used to produce RdRp for experimental work and the hidden impact that this has on enzyme activity and research outcomes. ABSTRACT The catalytic subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) Nsp12 has a unique nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain that transfers nucleoside monophosphates to the Nsp9 protein and the nascent RNA. The NiRAN and RdRp modules form a dynamic interface distant from their catalytic sites, and both activities are essential for viral replication. We report that codon-optimized (for the pause-free translation in bacterial cells) Nsp12 exists in an inactive state in which NiRAN-RdRp interactions are broken, whereas translation by slow ribosomes and incubation with accessory Nsp7/8 subunits or nucleoside triphosphates (NTPs) partially rescue RdRp activity. Our data show that adenosine and remdesivir triphosphates promote the synthesis of A-less RNAs, as does ppGpp, while amino acid substitutions at the NiRAN-RdRp interface augment activation, suggesting that ligand binding to the NiRAN catalytic site modulates RdRp activity. The existence of allosterically linked nucleotidyl transferase sites that utilize the same substrates has important implications for understanding the mechanism of SARS-CoV-2 replication and the design of its inhibitors. IMPORTANCE In vitro interrogations of the central replicative complex of SARS-CoV-2, RNA-dependent RNA polymerase (RdRp), by structural, biochemical, and biophysical methods yielded an unprecedented windfall of information that, in turn, instructs drug development and administration, genomic surveillance, and other aspects of the evolving pandemic response. They also illuminated the vast disparity in the methods used to produce RdRp for experimental work and the hidden impact that this has on enzyme activity and research outcomes. In this report, we elucidate the positive and negative effects of codon optimization on the activity and folding of the recombinant RdRp and detail the design of a highly sensitive in vitro assay of RdRp-dependent RNA synthesis. Using this assay, we demonstrate that RdRp is allosterically activated by nontemplating phosphorylated nucleotides, including naturally occurring alarmone ppGpp and synthetic remdesivir triphosphate.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"It is reported that codon-optimized Nsp12 exists in an inactive state in which NiRAN-RdRp interactions are broken, whereas translation by slow ribosomes and incubation with accessory Nsp7/8 subunits or nucleoside triphosphates (NTPs) partially rescue RdRp activity."}},"tag":"DRUG"},{"id":189,"details":{"paperId":"363d105f439431ae40539b573f657a63da9d764d","externalIds":{"MAG":"3007227604","PubMedCentral":"7089605","DOI":"10.1016/j.lfs.2020.117477","CorpusId":"211832172","PubMed":"32119961"},"title":"Anti-HCV, nucleotide inhibitors, repurposing against COVID-19","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"The results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease."}},"tag":"DRUG"},{"id":317,"details":{"paperId":"a9451cdea0bf598443d886f93a0d977d00c66ce1","externalIds":{"MAG":"3081918364","PubMedCentral":"7474075","DOI":"10.1038/s41467-020-18233-x","CorpusId":"221503125","PubMed":"32887884"},"title":"Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Efficient inhibition of SARS-CoV-2 replication using two inhibitors - Boceprevir and GC376 - targeting the active site of the main viral protease is reported."}},"tag":"DRUG"},{"id":234,"details":{"paperId":"037b8af7ade23b9d409d86f06545799592ce00ad","externalIds":{"PubMedCentral":"8610013","DOI":"10.1021/acschembio.1c00756","CorpusId":"244346241","PubMed":"34792325"},"title":"Clinical Antiviral Drug Arbidol Inhibits Infection by SARS-CoV-2 and Variants through Direct Binding to the Spike Protein","abstract":"Arbidol (ARB) is a broad-spectrum antiviral drug approved in Russia and China for the treatment of influenza. ARB was tested in patients as a drug candidate for the treatment at the early onset of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite promising clinical results and multiple ongoing trials, preclinical data are lacking and the molecular mechanism of action of ARB against SARS-CoV-2 remains unknown. Here, we demonstrate that ARB binds to the spike viral fusion glycoprotein of the SARS-CoV-2 Wuhan strain as well as its more virulent variants from the United Kingdom (strain B.1.1.7) and South Africa (strain B.1.351). We pinpoint the ARB binding site on the S protein to the S2 membrane fusion domain and use an infection assay with Moloney murine leukemia virus (MLV) pseudoviruses (PVs) pseudotyped with the S proteins of the Wuhan strain and the new variants to show that this interaction is sufficient for the viral cell entry inhibition by ARB. Finally, our experiments reveal that the ARB interaction leads to a significant destabilization and eventual lysosomal degradation of the S protein in cells. Collectively, our results identify ARB as the first clinically approved small molecule drug binder of the SARS-CoV-2 S protein and place ARB among the more promising drug candidates for COVID-19.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"These results identify ARB as the first clinically approved small molecule drug binder of the SARS-CoV-2 S protein and place ARB among the more promising drug candidates for COVID-19."}},"tag":"DRUG"},{"id":486,"details":{"paperId":"99b35a65a1519c83a48a7bb890ec5379a95cef77","externalIds":{"MAG":"3016403534","DOI":"10.1101/2020.04.13.038687","CorpusId":"216071474"},"title":"Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro","abstract":"Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a “shield” in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system."}},"tag":"DRUG"},{"id":57,"details":{"paperId":"026fecde9ded5672fd3afc307a3e88f181f19581","externalIds":{"PubMedCentral":"7839511","DOI":"10.1016/j.antiviral.2021.105020","CorpusId":"231721433","PubMed":"33515606"},"title":"Dual inhibition of SARS-CoV-2 and human rhinovirus with protease inhibitors in clinical development","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Structural analysis showed that the combination of minimal interactions, conformational flexibility, and limited bulk allows GC376 and calpain inhibitor II to potently inhibit both enzymes, which can guide the design of cysteine protease inhibitors that are either virus-specific or retain a broad antiviral spectrum against coronaviruses and rhinoviruses."}},"tag":"DRUG"},{"id":491,"details":{"paperId":"bf4fae81d34b6c1c4fbbf59bc19b6a59e03f2326","externalIds":{"MAG":"3024246131","DOI":"10.1101/2020.05.17.100768","CorpusId":"218764887"},"title":"Ebselen as a highly active inhibitor of PLProCoV2","abstract":"Since December 2019 a novel a coronavirus identified as SARS-CoV-2 or COV2 has been spreading around the world. On the 16th of May around 4.5 million people got infected and over 300,000 died due to the infection of COV2. The effective treatment remains a challenge. Targeted therapeutics are still under investigation. The papain-like protease (PLPro) from the human SARS-CoV-2 coronavirus is a cysteine protease that plays a critical role in virus replication. Its activity is required to process the viral polyprotein into functional, mature subunits. Moreover, COV2 uses this enzyme to modulate the host’s immune system to its own benefit. Therefore, it represents a highly promising target for the development of antiviral drugs. In this work, we discovered that ebselen, a synthetic organoselenium drug molecule with anti-inflammatory, anti-oxidant and cytoprotective activity in mammalian cells and cytotoxicity in lower organisms, is a highly active inhibitor of PLProCoV2. We proved that ebselen is a covalent, fast-binding inhibitor of PLProCoV2 exhibiting a low micromolar potency. Furthermore, we identified a difference between PLPro from SARS-CoV-1 (the corona virus which caused the 2002–2004 outbreak, SARS) and SARS-CoV-2 that allows to explain the difference in dynamics of the replication, and, thus, the disease progression. Namely, we present that they show differences in the binding affinity of substrates that we observed through kinetics and molecular docking studies. Using a novel Approximate Bayesian Computation method we were able to find kinetic constants for both enzymes. Molecular modeling study on the structure of the active site and binding mode of the ebselen with SARS and COV2 showed also significant differences that could explain our observation that ebselen is less active and slower bounding with SARS than COV2. In conclusion, we show that ebselen inhibits the activity of the essential viral enzyme papain-like protease (PLpro) from SARS-COV-2 in low micromolar range.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"Ebselen inhibits the activity of the essential viral enzyme papain-like protease (PLpro) from SARS-COV-2 in low micromolar range, which could explain the observation that ebselen is less active and slower bounding with SARS than COV2."}},"tag":"DRUG"},{"id":241,"details":{"paperId":"cdd6c9f3c063723b52e1ae230675513ad80877ea","externalIds":{"PubMedCentral":"8146138","DOI":"10.1021/acs.jafc.1c02050","CorpusId":"235074730","PubMed":"34015930"},"title":"Epigallocatechin Gallate Inhibits the Uridylate-Specific Endoribonuclease Nsp15 and Efficiently Neutralizes the SARS-CoV-2 Strain","abstract":"SARS-CoV-2, the coronavirus strain that initiated the COVID-19 pandemic, and its subsequent variants present challenges to vaccine development and treatment. As the coronavirus evades the host innate immune response at the initial stage of infection, the disease can have a long nonsymptomatic period. The uridylate-specific endoribonuclease Nsp15 processes the viral genome for replication and cleaves the polyU sequence in the viral RNA to interfere with the host immune system. This study screened natural compounds in vitro to identify inhibitors against Nsp15 from SARS-CoV-2. Three natural compounds, epigallocatechin gallate (EGCG), baicalin, and quercetin, were identified as potential inhibitors. Potent antiviral activity of EGCG was confirmed in plaque reduction neutralization tests with a SARS-CoV-2 strain (PRNT50 = 0.20 μM). Because the compound has been used as a functional food ingredient due to its beneficial health effects, we theorize that this natural compound may help inhibit viral replication while minimizing safety issues.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Three natural compounds, epigallocatechin gallate, baicalin, and quercetin, were identified as potential inhibitors against Nsp15 from SARS-CoV-2 and it is theorized that this natural compound may help inhibit viral replication while minimizing safety issues."}},"tag":"DRUG"},{"id":27,"details":{"paperId":"4ac687f11f9f047c8e9e1019b6b3a32582bbc7c5","externalIds":{"DOI":"10.1002/smll.202105640","CorpusId":"244907810","PubMed":"34866333"},"title":"Extracellular Vimentin as a Target Against SARS-CoV-2 Host Cell Invasion.","abstract":"Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. The primary receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2), yet new studies reveal the importance of additional extracellular co-receptors that mediate binding and host cell invasion by SARS-CoV-2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens' cellular uptake. Biophysical and cell infection studies are done to determine whether vimentin might bind SARS-CoV-2 and facilitate its uptake. Dynamic light scattering shows that vimentin binds to pseudovirus coated with the SARS-CoV-2 spike protein, and antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cells. The results are consistent with a model in which extracellular vimentin acts as a co-receptor for SARS-CoV-2 spike protein with a binding affinity less than that of the spike protein with ACE2. Extracellular vimentin may thus serve as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry, and vimentin-targeting agents may yield new therapeutic strategies for preventing and slowing SARS-CoV-2 infection.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Results are consistent with a model in which extracellular vimentin acts as a co-receptor for SARS-CoV-2 spike protein-ACE2 complex with a binding affinity less than that of the spike protein with ACE2."}},"tag":"DRUG"},{"id":546,"details":{"paperId":"55ccdbeb121595cb0da086f084a8cc921f13d6e6","externalIds":{"DOI":"10.1101/2020.12.20.423603","CorpusId":"229549696"},"title":"Fatty Acid Synthase inhibition prevents palmitoylation of SARS-CoV2 Spike Protein and improves survival of mice infected with murine hepatitis virus","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the causative agent of COVID19 that has infected >76M people and caused >1.68M deaths. The SARS-CoV2 Spike glycoprotein is responsible for the attachment and infection of target cells. The viral Spike protein serves the basis for many putative therapeutic countermeasures including vaccines, blocking and neutralizing antibodies, and decoy receptors. Here we investigated the cytosolic domain of Spike and its interaction with the protein palmitoyltransferase ZDHHC5. The Spike protein is palmitoylated on multiple juxtamembrane cysteine residues conserved among coronavirus. Increased abundance of ZDHHC5 resulted in hyper-palmitoylation, while silencing of ZDHHC5 reduced the ability of the human CoV 229E to form viral plaques in cell monolayers. Inhibition of fatty acid synthase using the pharmacological inhibitor TVB-3166 eliminated palmitoylation of SARS-CoV2 Spike. Additionally, TVB-3166 attenuated plaque formation and promoted the survival of mice from a lethal murine CoV infection. Thus, inhibition of the Spike protein palmitoylation has the potential to treat SARS-CoV-2 and other CoV infections.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"Inhibition of fatty acid synthase using the pharmacological inhibitor TVB-3166 eliminated palmitoylation of SARS-CoV2 Spike and attenuated plaque formation and promoted the survival of mice from a lethal murine CoV infection."}},"tag":"DRUG"},{"id":439,"details":{"paperId":"55fb28cfd8f918946be91ed49ba417def83ae01d","externalIds":{"MAG":"3047100065","PubMedCentral":"7470085","DOI":"10.1080/14756366.2020.1801672","CorpusId":"221704329","PubMed":"32746637"},"title":"Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro","abstract":"Abstract Coronavirus disease 2019 (COVID-19) has been a pandemic disease of which the termination is not yet predictable. Currently, researches to develop vaccines and treatments is going on globally to cope with this disastrous disease. Main protease (3CLpro) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the good targets to find antiviral agents before vaccines are available. Some flavonoids are known to inhibit 3CLpro from SARS-CoV which causes SARS. Since their sequence identity is 96%, a similar approach was performed with a flavonoid library. Baicalin, herbacetin, and pectolinarin have been discovered to block the proteolytic activity of SARS-CoV-2 3CLpro. An in silico docking study showed that the binding modes of herbacetin and pectolinarin are similar to those obtained from the catalytic domain of SARS-CoV 3CLpro. However, their binding affinities are different due to the usage of whole SARS-CoV-2 3CLpro in this study. Baicalin showed an effective inhibitory activity against SARS-CoV-2 3CLpro and its docking mode is different from those of herbacetin and pectolinarin. This study suggests important scaffolds to design 3CLpro inhibitors to develop antiviral agents or health-foods and dietary supplements to cope with SARS-CoV-2.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"This study suggests important scaffolds to design 3CLpro inhibitors to develop antiviral agents or health-foods and dietary supplements to cope with SARS-CoV-2."}},"tag":"DRUG"},{"id":144,"details":{"paperId":"6d39410623d1f931c84b58f156d17b8445012ddc","externalIds":{"PubMedCentral":"8074525","DOI":"10.1016/j.ijbiomac.2021.04.148","CorpusId":"233401326","PubMed":"33915212"},"title":"Heparin: A simplistic repurposing to prevent SARS-CoV-2 transmission in light of its in-vitro nanomolar efficacy","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Results of highly efficacious viral entry blocking properties of heparin in the complete virus assay are reported, and ways to use it as a potential transmission blocker are proposed to block SARS-CoV-2 transmission."}},"tag":"DRUG"},{"id":108,"details":{"paperId":"f0fc2192357f54cf57065e8985775bf77ff0a2d7","externalIds":{"PubMedCentral":"8075848","DOI":"10.1016/j.celrep.2021.109133","CorpusId":"233401316","PubMed":"33984267"},"title":"Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"This conundrum was resolved by demonstrating that four HCV protease inhibitor drugs inhibit the SARS CoV-2 papain-like protease (PLpro), while HCV drugs that inhibit PLpro synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesvir’s antiviral activity as much as 10-fold."}},"tag":"DRUG"},{"id":254,"details":{"paperId":"3bf90cd3228c33b0f9f84a6202232dc322dbb823","externalIds":{"MAG":"3083738738","PubMedCentral":"7507806","DOI":"10.1021/acsptsci.0c00108","CorpusId":"221836831","PubMed":"33062953"},"title":"Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-Throughput Screening","abstract":"The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emphasized the urgency to develop effective therapeutics. Drug repurposing screening is regarded as one of the most practical and rapid approaches for the discovery of such therapeutics. The 3C-like protease (3CLpro), or main protease (Mpro) of SARS-CoV-2 is a valid drug target as it is a specific viral enzyme and plays an essential role in viral replication. We performed a quantitative high-throughput screening (qHTS) of 10 755 compounds consisting of approved and investigational drugs, and bioactive compounds using a SARS-CoV-2 3CLpro assay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CLpro have been identified with IC50s ranging from 0.26 to 28.85 μM. Walrycin B (IC50 = 0.26 μM), hydroxocobalamin (IC50 = 3.29 μM), suramin sodium (IC50 = 6.5 μM), Z-DEVD-FMK (IC50 = 6.81 μM), LLL-12 (IC50 = 9.84 μM), and Z-FA-FMK (IC50 = 11.39 μM) are the most potent 3CLpro inhibitors. The activity of the anti-SARS-CoV-2 viral infection was confirmed in 7 of 23 compounds using a SARS-CoV-2 cytopathic effect assay. The results demonstrated a set of SARS-CoV-2 3CLpro inhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients and as starting points for chemistry optimization for new drug development.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"A set of SARS-CoV-2 3CLpro inhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients and as starting points for chemistry optimization for new drug development are demonstrated."}},"tag":"DRUG"},{"id":802,"details":{"paperId":"750b4f82ab1a035477650b5eb8d824026ee16f7c","externalIds":{"PubMedCentral":"8198929","DOI":"10.3390/molecules26113213","CorpusId":"235298266","PubMed":"34072087"},"title":"Identification of SARS-CoV-2 Receptor Binding Inhibitors by In Vitro Screening of Drug Libraries","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global pandemic. The first step of viral infection is cell attachment, which is mediated by the binding of the SARS-CoV-2 receptor binding domain (RBD), part of the virus spike protein, to human angiotensin-converting enzyme 2 (ACE2). Therefore, drug repurposing to discover RBD-ACE2 binding inhibitors may provide a rapid and safe approach for COVID-19 therapy. Here, we describe the development of an in vitro RBD-ACE2 binding assay and its application to identify inhibitors of the interaction of the SARS-CoV-2 RBD to ACE2 by the high-throughput screening of two compound libraries (LOPAC®1280 and DiscoveryProbeTM). Three compounds, heparin sodium, aurintricarboxylic acid (ATA), and ellagic acid, were found to exert an effective binding inhibition, with IC50 values ranging from 0.6 to 5.5 µg/mL. A plaque reduction assay in Vero E6 cells infected with a SARS-CoV-2 surrogate virus confirmed the inhibition efficacy of heparin sodium and ATA. Molecular docking analysis located potential binding sites of these compounds in the RBD. In light of these findings, the screening system described herein can be applied to other drug libraries to discover potent SARS-CoV-2 inhibitors.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"The development of an in vitro RBD-ACE2 binding assay and its application to identify inhibitors of the interaction of the SARS-CoV-2 RBD to ACE2 by the high-throughput screening of two compound libraries (LOPAC®1280 and DiscoveryProbeTM)."}},"tag":"DRUG"},{"id":277,"details":{"paperId":"e4dc0e26c522ac5869a310d32fc0cac1820c849a","externalIds":{"PubMedCentral":"7594953","MAG":"3097146219","DOI":"10.1038/s41401-020-00556-6","CorpusId":"226031711","PubMed":"33116249"},"title":"Identification of SARS-CoV-2 entry inhibitors among already approved drugs","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 drugs significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity."}},"tag":"DRUG"},{"id":392,"details":{"paperId":"80e4359b29f8653a5ab82711b91a10756de56f0f","externalIds":{"PubMedCentral":"7878891","DOI":"10.1038/s41598-021-83229-6","CorpusId":"231901875","PubMed":"33574416"},"title":"Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"A difference between PLpro from SARS and CoV2 that can be correlated with the diverse dynamics of their replication, and, putatively to disease progression, is found."}},"tag":"DRUG"},{"id":283,"details":{"paperId":"19e6431140ee702df28ab3048c4dd39d679a9b26","externalIds":{"PubMedCentral":"7987752","DOI":"10.1038/s41419-021-03513-1","CorpusId":"232336368","PubMed":"33762578"},"title":"Inhibition of HECT E3 ligases as potential therapy for COVID-19","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"The HECT family members of E3 ligases are identified as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds."}},"tag":"DRUG"},{"id":649,"details":{"paperId":"6d1b0c618dcdec59817838a7cdb2f43856d9da88","externalIds":{"PubMedCentral":"8844921","DOI":"10.1128/mbio.03718-21","CorpusId":"246814230","PubMed":"35164559"},"title":"Inhibition of Protein N-Glycosylation Blocks SARS-CoV-2 Infection","abstract":"The coronavirus SARS-CoV-2 uses its spike surface proteins to infect human cells. Spike proteins are heavily modified with several N-glycans, which are predicted to modulate their function. ABSTRACT Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) extensively N-glycosylates its spike proteins, which are necessary for host cell invasion and the target of both vaccines and immunotherapies. These N-glycans are predicted to modulate spike binding to the host receptor by stabilizing its open conformation and host immunity evasion. Here, we investigated the essentiality of both the host N-glycosylation pathway and SARS-CoV-2 N-glycans for infection. Ablation of host N-glycosylation using RNA interference or inhibitors, including FDA-approved drugs, reduced the spread of the infection, including that of variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). Under these conditions, cells produced fewer virions and some completely lost their infectivity. Furthermore, partial enzymatic deglycosylation of intact virions showed that surface-exposed N-glycans are critical for cell invasion. Altogether, we propose protein N-glycosylation as a targetable pathway with clinical potential for treatment of COVID-19. IMPORTANCE The coronavirus SARS-CoV-2 uses its spike surface proteins to infect human cells. Spike proteins are heavily modified with several N-glycans, which are predicted to modulate their function. In this work, we show that interfering with either the synthesis or attachment of spike N-glycans significantly reduces the spread of SARS-CoV-2 infection in vitro, including that of several variants. As new SARS-CoV-2 variants, with various degrees of resistance against current vaccines, are likely to continue appearing, halting virus glycosylation using repurposed human drugs could result in a complementary strategy to reducing the spread of COVID-19 worldwide.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"It is shown that interfering with either the synthesis or attachment of spike N-glycans significantly reduces the spread of SARS-CoV-2 infection in vitro, including that of several variants."}},"tag":"DRUG"},{"id":299,"details":{"paperId":"7a8043439e6e5bf9e39698ec7f0ba1b8291330c4","externalIds":{"PubMedCentral":"7104723","DOI":"10.1038/s41422-020-0305-x","CorpusId":"215095103"},"title":"Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion","abstract":null,"publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively."}},"tag":"DRUG"},{"id":558,"details":{"paperId":"8517aaebc3d742d02137e59645d5facaeedb488d","externalIds":{"DOI":"10.1101/2021.03.05.434000","CorpusId":"232169577","PubMed":"33688654"},"title":"Inhibition of amyloid formation of the Nucleoprotein of SARS-CoV-2","abstract":"The SARS-CoV-2 Nucleoprotein (NCAP) functions in RNA packaging during viral replication and assembly. Computational analysis of its amino acid sequence reveals a central low-complexity domain (LCD) having sequence features akin to LCDs in other proteins known to function in liquid–liquid phase separation. Here we show that in the presence of viral RNA, NCAP, and also its LCD segment alone, form amyloid-like fibrils when undergoing liquid–liquid phase separation. Within the LCD we identified three 6-residue segments that drive amyloid fibril formation. We determined atomic structures for fibrils formed by each of the three identified segments. These structures informed our design of peptide inhibitors of NCAP fibril formation and liquid–liquid phase separation, suggesting a therapeutic route for Covid-19. One Sentence Summary Atomic structures of amyloid-driving peptide segments from SARS-CoV-2 Nucleoprotein inform the development of Covid-19 therapeutics.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"It is shown that in the presence of viral RNA, NCAP, and also its LCD segment alone, form amyloid-like fibrils when undergoing liquid–liquid phase separation, suggesting a therapeutic route for Covid-19."}},"tag":"DRUG"},{"id":514,"details":{"paperId":"3f01cfc409d9ecf9c7e366ef9e28afad49a31a23","externalIds":{"PubMedCentral":"7430595","MAG":"3048573030","DOI":"10.1101/2020.08.12.246389","CorpusId":"221141815","PubMed":"32817953"},"title":"Maraviroc inhibits SARS-CoV-2 multiplication and s-protein mediated cell fusion in cell culture","abstract":"In an effort to identify therapeutic intervention strategies for the treatment of COVID-19, we have investigated a selection of FDA-approved small molecules and biologics that are commonly used to treat other human diseases. A investigation into 18 small molecules and 3 biologics was conducted in cell culture and the impact of treatment on viral titer was quantified by plaque assay. The investigation identified 4 FDA-approved small molecules, Maraviroc, FTY720 (Fingolimod), Atorvastatin and Nitazoxanide that were able to inhibit SARS-CoV-2 infection. Confocal microscopy with over expressed S-protein demonstrated that Maraviroc reduced the extent of S-protein mediated cell fusion as observed by fewer multinucleate cells in the context of drugtreatment. Mathematical modeling of drug-dependent viral multiplication dynamics revealed that prolonged drug treatment will exert an exponential decrease in viral load in a multicellular/tissue environment. Taken together, the data demonstrate that Maraviroc, Fingolimod, Atorvastatin and Nitazoxanide inhibit SARS-CoV-2 in cell culture.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"The investigation identified 4 FDA-approved small molecules, Maraviroc, FTY720 (Fingolimod), Atorvastatin and Nitazoxanide that were able to inhibit SARS-CoV-2 infection."}},"tag":"DRUG"},{"id":702,"details":{"paperId":"fe140cd4ec4538cf8d1cae980d628d7d26827884","externalIds":{"PubMedCentral":"7461020","MAG":"3080855264","DOI":"10.15252/embj.2020106275","CorpusId":"221328909","PubMed":"32845033"},"title":"Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2","abstract":"The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model."}},"tag":"DRUG"},{"id":229,"details":{"paperId":"c1e7360295f75f8d44256bfb2296251575637d44","externalIds":{"PubMedCentral":"8204756","DOI":"10.1021/acs.biochem.1c00292","CorpusId":"235393153","PubMed":"34110129"},"title":"Mechanism of Inhibition of the Reproduction of SARS-CoV-2 and Ebola Viruses by Remdesivir","abstract":"Remdesivir is an antiviral drug initially designed against the Ebola virus. The results obtained with it both in biochemical studies in vitro and in cell line assays in vivo were very promising, but it proved to be ineffective in clinical trials. Remdesivir exhibited far better efficacy when repurposed against SARS-CoV-2. The chemistry that accounts for this difference is the subject of this study. Here, we examine the hypothesis that remdesivir monophosphate (RMP)-containing RNA functions as a template at the polymerase site for the second run of RNA synthesis, and as mRNA at the decoding center for protein synthesis. Our hypothesis is supported by the observation that RMP can be incorporated into RNA by the RNA-dependent RNA polymerases (RdRps) of both viruses, although some of the incorporated RMPs are subsequently removed by exoribonucleases. Furthermore, our hypothesis is consistent with the fact that RdRp of SARS-CoV-2 selects RMP for incorporation over AMP by 3-fold in vitro, and that RMP-added RNA can be rapidly extended, even though primer extension is often paused when the added RMP is translocated at the i + 3 position (with i the nascent base pair at an initial insertion site of RMP) or when the concentrations of the subsequent nucleoside triphosphates (NTPs) are below their physiological concentrations. These observations have led to the hypothesis that remdesivir might be a delayed chain terminator. However, that hypothesis is challenged under physiological concentrations of NTPs by the observation that approximately three-quarters of RNA products efficiently overrun the pause.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"The hypothesis is examined that remdesivir monophosphate-containing RNA functions as a template at the polymerase site for the second run of RNA synthesis, and as mRNA at the decoding center for protein synthesis, supported by the observation that RMP can be incorporated into RNA by the RNA-dependent RNA polymerases of both viruses."}},"tag":"DRUG"},{"id":350,"details":{"paperId":"5f795476fd3f8ef85f38e9841a9649f4fcdd3517","externalIds":{"MAG":"3092266552","DOI":"10.1038/s41564-020-00802-x","CorpusId":"222216457","PubMed":"33028965"},"title":"Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Testing a set of metallodrugs and related compounds identifies ranitidine bismuth citrate, a commonly used drug for the treatment of Helicobacter pylori infection, as a potent anti-SARS-CoV-2 agent, both in vitro and in vivo."}},"tag":"DRUG"},{"id":767,"details":{"paperId":"b27f936386fd0ede9406ff2d43152c5a36fe177c","externalIds":{"PubMedCentral":"8631967","DOI":"10.3389/fimmu.2021.733921","CorpusId":"235249291","PubMed":"34858397"},"title":"Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1","abstract":"A hallmark of COVID-19 is a hyperinflammatory state that is associated with severity. Various anti-inflammatory therapeutics have shown mixed efficacy in treating COVID-19, and the mechanisms by which hyperinflammation occurs are not well understood. Previous research indicated that monocytes, a key innate immune cell, undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response in monocytes. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism that was associated with production of pro-inflammatory cytokines including interleukin-6 and tumor necrosis factor-α. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production in monocytes, and abrogated glycolytic and mitochondrial metabolism. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments in monocytes. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"The SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and met formin likewise suppresses inflammatory responses to live SARS, which has potential implications for the treatment of hyperinflammation during COVID-19."}},"tag":"DRUG"},{"id":164,"details":{"paperId":"db04c289ef6e70a594b109427c95bb2a4287f180","externalIds":{"PubMedCentral":"8110631","DOI":"10.1016/j.jbc.2021.100770","CorpusId":"234345322","PubMed":"33989635"},"title":"Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0"}},"tag":"DRUG"},{"id":451,"details":{"paperId":"e7951564577fc2b44d737c2559da55319ceb652a","externalIds":{"DOI":"10.1093/abbs/gmab088","CorpusId":"235609394","PubMed":"34159380"},"title":"Nsp2 has the potential to be a drug target revealed by global identification of SARS-CoV-2 Nsp2-interacting proteins.","abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health threat since December 2019, and there is still no highly effective drug to control the pandemic. To facilitate drug target identification for drug development, studies on molecular mechanisms, such as SARS-CoV-2 protein interactions, are urgently needed. In this study, we focused on Nsp2, a non-structural protein with largely unknown function and mechanism. The interactome of Nsp2 was revealed through the combination of affinity purification mass spectrometry (AP-MS) and stable isotope labeling by amino acids in cell culture (SILAC), and 84 proteins of high-confidence were identified. Gene ontology analysis demonstrated that Nsp2-interacting proteins are involved in several biological processes such as endosome transport and translation. Network analysis generated two clusters, including ribosome assembly and vesicular transport. Bio-layer interferometry (BLI) assay confirmed the bindings between Nsp2- and 4-interacting proteins, i.e. STAU2 (Staufen2), HNRNPLL, ATP6V1B2, and RAP1GDS1 (SmgGDS), which were randomly selected from the list of 84 proteins. Our findings provide insights into the Nsp2-host interplay and indicate that Nsp2 may play important roles in SARS-CoV-2 infection and serve as a potential drug target for anti-SARS-CoV-2 drug development.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"It is indicated that Nsp2 may play important roles in SARS-CoV-2 infection and serve as a potential drug target for anti-SARS- covirus 2 drug development."}},"tag":"DRUG"},{"id":45,"details":{"paperId":"180338bfe4cee412398fffb9080af26e27f00660","externalIds":{"PubMedCentral":"8014903","DOI":"10.1007/s12013-021-00977-y","CorpusId":"232480193","PubMed":"33792836"},"title":"Piece of the puzzle: Remdesivir disassembles the multimeric SARS-CoV-2 RNA-dependent RNA polymerase complex","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Novel mechanisms that may underlie the binding of Rem-P3 to SARS-CoV-2 RdRp-NSPs complex; a multimeric assembly that drives viral RNA replication in human hosts are theorized using computational simulations."}},"tag":"DRUG"},{"id":139,"details":{"paperId":"fe400a855581c620146df48b0ea1f0f6b197df28","externalIds":{"MAG":"3123421077","PubMedCentral":"7826122","DOI":"10.1016/j.ejmech.2021.113201","CorpusId":"231689886","PubMed":"33524687"},"title":"RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic","abstract":null,"publicationTypes":["Review","JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"This review describes the promising RdRp inhibitors that have been launched or are currently in clinical studies for the treatment of RNA virus infections and suggests more precise guidelines for the development of more promising anti-RNA virus drugs should be set."}},"tag":"DRUG"},{"id":415,"details":{"paperId":"0e1c566cde789e1fc9e42c8a44f7210129676328","externalIds":{"PubMedCentral":"7604432","MAG":"3092050068","DOI":"10.1073/pnas.2012294117","CorpusId":"222216832","PubMed":"33028676"},"title":"Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases","abstract":"Significance Remdesivir is a nucleotide analog prodrug that has been evaluated in humans against acute Ebola virus disease; it also recently received emergency use authorization for treating COVID-19. For antiviral product development, the Food and Drug Administration recommends the characterization of in vitro selected resistant viruses to define the specific antiviral mechanism of action. This study identified a single amino acid residue in the Ebola virus polymerase that conferred low-level resistance to remdesivir. The significance of our study lies not only in characterizing this particular mutation, but also in relating it to a resistance mutation observed in a similar structural motif of coronaviruses. Our findings thereby indicate a consistent mechanism of action by remdesivir across genetically divergent RNA viruses causing diseases of high consequence in humans. Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. With approvals from the Federal Select Agent Program and the Centers for Disease Control and Prevention’s Institutional Biosecurity Board, we characterized the resistance profile of remdesivir by serially passaging Ebola virus under remdesivir selection; we generated lineages with low-level reduced susceptibility to remdesivir after 35 passages. We found that a single amino acid substitution, F548S, in the Ebola virus polymerase conferred low-level reduced susceptibility to remdesivir. The F548 residue is highly conserved in filoviruses but should be subject to specific surveillance among novel filoviruses, in newly emerging variants in ongoing outbreaks, and also in Ebola virus patients undergoing remdesivir therapy. Homology modeling suggests that the Ebola virus polymerase F548 residue lies in the F-motif of the polymerase active site, a region that was previously identified as susceptible to resistance mutations in coronaviruses. Our data suggest that molecular surveillance of this region of the polymerase in remdesivir-treated COVID-19 patients is also warranted.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"This study identified a single amino acid residue in the Ebola virus polymerase that conferred low-level resistance to remdesivir, indicating a consistent mechanism of action by remdesvir across genetically divergent RNA viruses causing diseases of high consequence in humans."}},"tag":"DRUG"},{"id":606,"details":{"paperId":"27fee369ec73f726406dd30cccca36ad5adcc220","externalIds":{"PubMedCentral":"8099175","DOI":"10.1126/science.abf1611","CorpusId":"231963585","PubMed":"33602867"},"title":"SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model","abstract":"Targeting the SARS-CoV-2 main protease Vaccines are an important tool in the fight against COVID-19, but developing antiviral drugs is also a high priority, especially with the rise of variants that may partially evade vaccines. The viral protein main protease is required for cleaving precursor polyproteins into functional viral proteins. This essential function makes it a key drug target. Qiao et al. designed 32 inhibitors based on either boceprevir or telaprevir, both of which are protease inhibitors approved to treat hepatitis C virus. Six compounds protected cells from viral infection with high potency, and two of these were selected for in vivo studies based on pharmokinetic experiments. Both showed strong antiviral activity in a mouse model. Science, this issue p. 1374 Designed SARS-CoV-2 Mpro (main protease) inhibitors display excellent antiviral activity both in vitro and in a transgenic mouse model. The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals are designed and synthesized and display excellent antiviral activity both in vitro and in a transgenic mouse model."}},"tag":"DRUG"},{"id":218,"details":{"paperId":"f2b0129dee639becfe62c668e4d851e1397be4f0","externalIds":{"PubMedCentral":"7834001","MAG":"3093044173","DOI":"10.1016/j.xinn.2021.100080","CorpusId":"225056905","PubMed":"33521757"},"title":"Structural Basis of SARS-CoV-2 Polymerase Inhibition by Favipiravir","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"The cryo-EM structure of Favipiravir bound to the replicating polymerase complex of SARS-CoV-2 in the pre-catalytic state is determined to shed lights on the mechanism of coronavirus polymerase catalysis and provide a rational basis for developing antiviral drugs to combat the Sars-Cov-2 pandemic."}},"tag":"DRUG"},{"id":598,"details":{"paperId":"26afe30e374304de897a206b05f86e5c0e729b09","externalIds":{"MAG":"3015431764","PubMedCentral":"7199908","DOI":"10.1126/science.abc1560","CorpusId":"215791091","PubMed":"32358203"},"title":"Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir","abstract":"A wrench in the works of COVID-19 Understanding the inner workings of the virus that causes coronavirus disease 2019 (COVID-19) may help us to disrupt it. Yin et al. focused on the viral polymerase essential for replicating viral RNA. They determined a structure of the polymerase bound to RNA and to the drug remdesivir. Remdesivir mimics an RNA nucleotide building block and is covalently linked to the replicating RNA, which blocks further synthesis of RNA. The structure provides a template for designing improved therapeutics against the viral polymerase. Science, this issue p. 1499 Cryo-EM structures show how the drug remdesivir binds to the RNA polymerase to block RNA elongation. The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo–electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Cryo–electron microscopy structures of the SARS-CoV-2 RdRp provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection."}},"tag":"DRUG"},{"id":506,"details":{"paperId":"ae4128750261be508361e38240365098565f3e1b","externalIds":{"MAG":"3042497846","DOI":"10.1101/2020.07.17.208959","CorpusId":"220650949"},"title":"Structural basis for the inhibition of the papain-like protease of SARS-CoV-2 by small molecules","abstract":"SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease has been implicated in virus maturation, dysregulation of host inflammation and antiviral immune responses. We showed that PLpro preferably cleaves the K48-ubiquitin linkage while also being capable of cleaving ISG15 modification. The multiple functions of PLpro render it a promising drug target. Therefore, we screened an FDA-approved drug library and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising IC50 of 2.1 μM. The co-crystal structure of SARS-CoV-2 PLpro-C111S in complex with GRL0617 suggests that GRL0617 is a non-covalent inhibitor. NMR data indicate that GRL0617 blocks the binding of ISG15 to PLpro. The antiviral activity of GRL0617 reveal that PLpro is a promising drug target for therapeutically treating COVID-19. One Sentence Summary Co-crystal structure of PLpro in complex with GRL0617 reveals the druggability of PLpro for SARS-CoV-2 treatment.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"It is shown that PLpro preferably cleaves the K48-ubiquitin linkage while also being capable of cleaving ISG15 modification, which renders it a promising drug target for therapeutically treating COVID-19."}},"tag":"DRUG"},{"id":326,"details":{"paperId":"4422843690116b2bd5dc8404504d707b0fbbf8a6","externalIds":{"MAG":"3047160870","DOI":"10.1038/s41467-021-21060-3","CorpusId":"225368240","PubMed":"33531496"},"title":"Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"A substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the SARS-CoV-2 enzyme are reported and crystal structures of PLpro in its apo state and with the bound inhibitors are presented, which are of interest for further structure-based drug design efforts."}},"tag":"DRUG"},{"id":482,"details":{"paperId":"59c9635f2355818d531d77c0ff0e2b4a09c93fa3","externalIds":{"MAG":"3102630149","DOI":"10.1101/2020.03.07.981928","CorpusId":"219604002"},"title":"Substrate specificity profiling of SARS-CoV-2 main protease enables design of activity-based probes for patient-sample imaging","abstract":"In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective antiviral treatment for coronavirus disease 2019 (COVID-19); therefore, research efforts are focused on the rapid development of vaccines and antiviral drugs. The SARS-CoV-2 main protease constitutes one of the most attractive antiviral drug targets. To address this emerging problem, we have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases, using natural and a large panel of unnatural amino acids. On the basis of these findings, we designed and synthesized an inhibitor and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. Using this approach we visualized SARS-CoV-2 active Mpro within nasopharyngeal epithelial cells of a patient with active COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents or diagnostic tests.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"A combinatorial library of fluorogenic substrates with glutamine in the P1 position is synthesized and provided a structural framework for the design of inhibitors as antiviral agents or diagnostic tests."}},"tag":"DRUG"},{"id":498,"details":{"paperId":"f4ce09ffa0fbe119a840bcdcef017add7fea7950","externalIds":{"MAG":"3106134797","DOI":"10.1101/2020.06.24.169334","CorpusId":"225062600"},"title":"Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 By Disrupting The Spike-ACE2 interaction","abstract":"Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a co-receptor with the ACE2 protein for recognition of the S1 spike protein on SARS-CoV2 virus, revealing an attractive new target for therapeutic intervention. Clinically-used heparins demonstrate relevant inhibitory activity, but world supplies are limited, necessitating a synthetic solution. The HS mimetic pixatimod is synthetic drug candidate for cancer with immunomodulatory and heparanase-inhibiting properties. Here we show that pixatimod binds directly to the SARS-CoV-2 spike protein receptor binding domain (S1-RBD), altering its conformation and destabilizing its structure. Molecular modelling identified a binding site overlapping with the ACE2 receptor site. Consistent with this, pixatimod inhibits binding of S1-RBD to ACE2-expressing cells and displays a direct mechanism of action by inhibiting binding of S1-RBD to human ACE2. Assays with four different clinical isolates of live SARS-CoV-2 virus show that pixatimod potently inhibits infection of Vero cells at doses well within its safe therapeutic dose range. This demonstration of potent anti-SARS-CoV-2 activity establishes that synthetic HS mimetics can target the HS-Spike protein-ACE2 axis. Together with other known activities of pixatimod our data provides a strong rationale for its further investigation as a potential multimodal therapeutic to address the COVID-19 pandemic.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"Assays with four different clinical isolates of live SARS-CoV-2 virus show that pixatimod potently inhibits infection of Vero cells at doses well within its safe therapeutic dose range, establishing that synthetic HS mimetics can target the HS-Spike protein-ACE2 axis."}},"tag":"DRUG"},{"id":84,"details":{"paperId":"00945745d3068c07c6a4ad340370feb8438cba9e","externalIds":{"PubMedCentral":"7889471","DOI":"10.1016/j.cbi.2021.109420","CorpusId":"231946612","PubMed":"33609497"},"title":"Testing of the inhibitory effects of loratadine and desloratadine on SARS-CoV-2 spike pseudotyped virus viropexis","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"This study is the first to demonstrate the inhibitory effect of LOR and DES on SARS-CoV-2 spike pseudotyped virus viropexis by blocking spike protein–ACE2 interaction and may provide a new strategy for finding an effective therapeutic option for COVID-19."}},"tag":"DRUG"},{"id":808,"details":{"paperId":"e5dc3124bdad6aafdbd60d4a01b9448aaf577bf5","externalIds":{"PubMedCentral":"7354595","MAG":"3033543683","DOI":"10.3390/v12060629","CorpusId":"219621958","PubMed":"32532094"},"title":"The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner","abstract":"Although infection by SARS-CoV-2, the causative agent of coronavirus pneumonia disease (COVID-19), is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked Middle East respiratory syndrome coronavirus (MERS-CoV) S protein-mediated cell fusion by targeting transmembrane serine protease 2 (TMPRSS2), and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (ACE2) and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an effective concentration (EC)50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC50 around 30 μM) was required for VeroE6/TMPRSS2 cells, where the TMPRSS2-independent but cathepsin-dependent endosomal infection pathway likely predominates. Together, our study shows that nafamostat mesylate potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and also inhibits SARS-CoV-2 infection in vitro in a cell-type-dependent manner. These findings, together with accumulated clinical data regarding nafamostat’s safety, make it a likely candidate drug to treat COVID-19.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"A quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (ACE2) and TMPRSS2 is established, and nafamostat mesylate potently inhibited the fusion while camostat Mesylate was about 10-fold less active, making it a likely candidate drug to treat COVID-19."}},"tag":"DRUG"},{"id":517,"details":{"paperId":"3fd887bbf1178f1ced49551888df37abe245b09b","externalIds":{"MAG":"3113241844","DOI":"10.1101/2020.08.14.251207","CorpusId":"229549364"},"title":"The FDA-approved drug Alectinib compromises SARS-CoV-2 nucleocapsid phosphorylation and inhibits viral infection in vitro","abstract":"While vaccines are vital for preventing COVID-19 infections, it is critical to develop new therapies to treat patients who become infected. Pharmacological targeting of a host factor required for viral replication can suppress viral spread with a low probability of viral mutation leading to resistance. In particular, host kinases are highly druggable targets and a number of conserved coronavirus proteins, notably the nucleoprotein (N), require phosphorylation for full functionality. In order to understand how targeting kinases could be used to compromise viral replication, we used a combination of phosphoproteomics and bioinformatics as well as genetic and pharmacological kinase inhibition to define the enzymes important for SARS-CoV-2 N protein phosphorylation and viral replication. From these data, we propose a model whereby SRPK1/2 initiates phosphorylation of the N protein, which primes for further phosphorylation by GSK-3α/β and CK1 to achieve extensive phosphorylation of the N protein SR-rich domain. Importantly, we were able to leverage our data to identify an FDA-approved kinase inhibitor, Alectinib, that suppresses N phosphorylation by SRPK1/2 and limits SARS-CoV-2 replication. Together, these data suggest that repurposing or developing novel host-kinase directed therapies may be an efficacious strategy to prevent or treat COVID-19 and other coronavirus-mediated diseases.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"The data suggest that repurposing or developing novel host-kinase directed therapies may be an efficacious strategy to prevent or treat COVID-19 and other coronavirus-mediated diseases."}},"tag":"DRUG"},{"id":162,"details":{"paperId":"b443ec72de38f7a492892404edd6df87fc8602f6","externalIds":{"PubMedCentral":"7566794","MAG":"3093454821","DOI":"10.1016/j.jacbts.2020.10.003","CorpusId":"222804835","PubMed":"33102950"},"title":"The Integrin Binding Peptide, ATN-161, as a Novel Therapy for SARS-CoV-2 Infection","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"This work focuses on the potential to inhibit SARS-CoV-2 entry through a hypothesized α5β1 integrin-based mechanism, and indicates that inhibiting the spike protein interaction with α5 β1Integrin (+/- ACE2), and the interaction between α5α2 integrin and ACE2 using a novel molecule ATN-161 represents a promising approach to treat COVID-19."}},"tag":"DRUG"},{"id":239,"details":{"paperId":"d411630dbe86e14c074414d149cc8bbfff62ac0d","externalIds":{"PubMedCentral":"8265718","MAG":"3130998288","DOI":"10.1021/acsinfecdis.1c00131","CorpusId":"233974468","PubMed":"34152728"},"title":"The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors","abstract":"In this study, we have focused on the structure-based design of the inhibitors of one of the two SARS-CoV-2 methyltransferases (MTases), nsp14. This MTase catalyzes the transfer of the methyl group from S-adenosyl-l-methionine (SAM) to cap the guanosine triphosphate moiety of the newly synthesized viral RNA, yielding the methylated capped RNA and S-adenosyl-l-homocysteine (SAH). As the crystal structure of SARS-CoV-2 nsp14 is unknown, we have taken advantage of its high homology to SARS-CoV nsp14 and prepared its homology model, which has allowed us to identify novel SAH derivatives modified at the adenine nucleobase as inhibitors of this important viral target. We have synthesized and tested the designed compounds in vitro and shown that these derivatives exert unprecedented inhibitory activity against this crucial enzyme. The docking studies nicely explain the contribution of an aromatic part attached by a linker to the position 7 of the 7-deaza analogues of SAH.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"Novel SAH derivatives modified at the adenine nucleobase as inhibitors of this important viral target are identified and synthesized and tested in vitro and shown that these derivatives exert unprecedented inhibitory activity against this crucial enzyme."}},"tag":"DRUG"},{"id":10,"details":{"paperId":"b391aae1f05190c55903b91b7baaa323df459158","externalIds":{"PubMedCentral":"7267418","MAG":"3017874111","DOI":"10.1002/jmv.25985","CorpusId":"218466197","PubMed":"32374457"},"title":"The anti‐HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV‐2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID‐19 infections","abstract":"Coronaviruses belong to a group of enveloped, positive-single stranded RNA viruses that are known to cause severe respiratory distress in animals and humans. The current SARS coronavirus-2 (SARS CoV-2) pandemic has caused more than 2,000,000 infections globally and nearly 200,000 deaths. Coronaviruses enter susceptible cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after endocytosis of the virus into endosomes. Previous results with SARS and MERS CoV have shown that the Spike (S) glycoprotein is a major determinant of virus infectivity and immunogenicity. Herein, we show that expression of SARS CoV-2 S (S-n) glycoprotein after transient transfection of African green monkey kidney (Vero) cells caused extensive cell fusion in comparison to limited cell fusion caused by the SARS S (S-o) glycoprotein. S-n expression was detected intracellularly and on transfected Vero cell surfaces and caused the formation of very large multinucleated cells (syncytia) by 48 hours post transfection. These results are in agreement with published pathology observations of extensive syncytial formation in lung tissues of COVID-19 patients. This differential S-n versus S-o-mediated cell fusion suggests that SARS-CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular spaces and neutralizing antibodies. A systematic screening of several drugs for ability to inhibit S-n and S-o cell fusion revealed that the FDA approved HIV-protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S-n and S-o-mediated cell fusion in a dose-dependent manner. Complete inhibition of cell fusion was observed at a 10 micromolar concentration. Computational modeling and in silico docking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S-n and S-o-mediated membrane fusion. Also, it is possible that nelfinavir mesylate acts on cellular processes to inhibit S proteolytic processing. These results warrant further investigations of the potential of nelfinavir mesylate as an antiviral drug, especially at early times after SARS-CoV-2 symptoms appear.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"This differential S-n versus S-o-mediated cell fusion suggests that SARS-CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular spaces and neutralizing antibodies."}},"tag":"DRUG"},{"id":721,"details":{"paperId":"319a2899e26553944821735d0178780322658c9c","externalIds":{"DOI":"10.2210/pdb6lu7/pdb","CorpusId":"241255971"},"title":"The crystal structure of COVID-19 main protease in complex with an inhibitor N3","abstract":null,"publicationTypes":null,"tldr":null},"tag":"DRUG"},{"id":156,"details":{"paperId":"bcfd1790a20409c2b137b0ad825e58f32a37b7bb","externalIds":{"PubMedCentral":"8277956","MAG":"3093027097","DOI":"10.1016/j.isci.2021.102857","CorpusId":"224819951","PubMed":"34278249"},"title":"The strand-biased transcription of SARS-CoV-2 and unbalanced inhibition by remdesivir","abstract":null,"publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"This study deeply sequenced both strands of RNA and found SARS-CoV-2 transcription is strongly biased to form the sense strand, which may facilitate the anti-viral vaccine development and drug design."}},"tag":"DRUG"},{"id":481,"details":{"paperId":"2f1644b5a2b9e81c95d1550492af8666c4fe08a2","externalIds":{"MAG":"3005556888","DOI":"10.1101/2020.02.08.926006","CorpusId":"229171178"},"title":"The transmembrane serine protease inhibitors are potential antiviral drugs for 2019-nCoV targeting the insertion sequence-induced viral infectivity enhancement","abstract":"In December 2019, 2019 novel coronavirus (2019-nCoV) induced an ongoing outbreak of pneumonia in Wuhan, Hubei, China. It enters into host cell via cellular receptor recognization and membrane fusion. The former is based on angiotensin converting enzyme II (ACE2). In the latter process, type II transmembrane serine proteases (TTSPs) play important roles in spike protein cleavage and activation. In this study, we used the single-cell transcriptomes of normal human lung and gastroenteric system to identify the ACE2- and TTSP-coexpressing cell composition and proportion. The results revealed that TMPRSS2 was highly co-expressed with ACE2 in the absorptive enterocytes, upper epithelial cells of esophagus and lung AT2 cells, implying the important role of TMPRSS2 in 2019-nCoV infection. Additionally, sequence and structural alignment showed that 675-QTQTNSPRRARSVAS-679 was the key sequence mediating 2019-nCoV spike protein, and there was a inserted sequence (680-SPRR-683). We speculated that this insertion sequence especially the exposed structure at R682 and R683 may enhance the recognition and cleavage activity of TMPRSS2 and then increase its viral infectivity. In conclusion, this study provides the bioinformatics and structure evidence for the increased viral infectivity of 2019-nCoV and indicates transmembrane serine protease inhibitors as the antiviral treatment options for 2019-nCoV infection targeting TMPRSS2.","publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"Transmembrane serine protease inhibitors as the antiviral treatment options for 2019-nCoV infection targeting TMPRSS2 are indicated and bioinformatics and structure evidence for the increased viral infectivity of 2019- nCoV is provided."}},"tag":"DRUG"},{"id":805,"details":{"paperId":"6e38e9c0593ca387801f0aad754177f40aa3a44a","externalIds":{"PubMedCentral":"8544662","DOI":"10.3390/ncrna7040060","CorpusId":"239886520","PubMed":"34698261"},"title":"Therapeutic Significance of microRNA-Mediated Regulation of PARP-1 in SARS-CoV-2 Infection","abstract":"The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 (2019-nCoV) has devastated global healthcare and economies. Despite the stabilization of infectivity rates in some developed nations, several countries are still under the grip of the pathogenic viral mutants that are causing a significant increase in infections and hospitalization. Given this urgency, targeting of key host factors regulating SARS-CoV-2 life cycle is postulated as a novel strategy to counter the virus and its associated pathological outcomes. In this regard, Poly (ADP)-ribose polymerase-1 (PARP-1) is being increasingly recognized as a possible target. PARP-1 is well studied in human diseases such as cancer, central nervous system (CNS) disorders and pathology of RNA viruses. Emerging evidence indicates that regulation of PARP-1 by non-coding RNAs such as microRNAs is integral to cell survival, redox balance, DNA damage response, energy homeostasis, and several other cellular processes. In this short perspective, we summarize the recent findings on the microRNA/PARP-1 axis and its therapeutic potential for COVID-19 pathologies.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"In this short perspective, the recent findings on the microRNA/PARP-1 axis and its therapeutic potential for COVID-19 pathologies are summarized."}},"tag":"DRUG"},{"id":400,"details":{"paperId":"495405488b2267aa3b77bf188e9ddca1be42882c","externalIds":{"DOI":"10.1038/s42003-021-01735-9","CorpusId":"257085710"},"title":"Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2","abstract":null,"publicationTypes":null,"tldr":{"model":"tldr@v2.0.0","text":"It is demonstrated that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme’s active site, providing new insights for the development of uracil scaffold-based drugs."}},"tag":"DRUG"},{"id":751,"details":{"paperId":"29946fb72eec9fe73f1ddb9b7c7c3628100a9dac","externalIds":{"DOI":"10.31083/j.fbl2701003","CorpusId":"245739469","PubMed":"35090308"},"title":"UV-4B potently inhibits replication of multiple SARS-CoV-2 strains in clinically relevant human cell lines.","abstract":"BACKGROUND\nSARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic. Although it poses a substantial public health threat, antiviral regimens against SARS-CoV-2 remain scarce. Here, we evaluated the antiviral potential of UV-4B, a host targeting antiviral, against SARS-CoV-2 in clinically relevant human cell lines.\n\n\nMETHODS\nCells derived from human lung (A549 cells transfected with human angiotensin converting enzyme 2 receptor (ACE2; ACE2-A549)) and colon (Caco-2) were infected with either a wild type or beta variant strain of SARS-CoV-2 and exposed to various concentrations of UV-4B. Supernatant was sampled daily and viral burden was quantified by plaque assay on Vero E6 cells.\n\n\nRESULTS\nTherapeutically feasible concentrations of UV-4B inhibited the replication of the wild type strain in ACE2-A549 and Caco-2 cells yielding EC50 values of 2.694 and 2.489 μM, respectively. UV-4B's antiviral effect was also robust against the beta variant in both cell lines (ACE2-A549 EC50: 4.369 μM; Caco-2 EC50: 6.816 μM).\n\n\nCONCLUSIONS\nThese results highlight UV-4B's antiviral potential against several strains of SARS-CoV-2.","publicationTypes":["JournalArticle"],"tldr":null},"tag":"DRUG"},{"id":608,"details":{"paperId":"d41adaad9a2aab87b8c1370925fe7540769cf517","externalIds":{"PubMedCentral":"8224385","DOI":"10.1126/science.abf7945","CorpusId":"232772574","PubMed":"33811162"},"title":"X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease","abstract":"A large-scale screen to target SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is initially expressed as two large polyproteins. Its main protease, Mpro, is essential to yield functional viral proteins, making it a key drug target. Günther et al. used x-ray crystallography to screen more than 5000 compounds that are either approved drugs or drugs in clinical trials. The screen identified 37 compounds that bind to Mpro. High-resolution structures showed that most compounds bind at the active site but also revealed two allosteric sites where binding of a drug causes conformational changes that affect the active site. In cell-based assays, seven compounds had antiviral activity without toxicity. The most potent, calpeptin, binds covalently in the active site, whereas the second most potent, pelitinib, binds at an allosteric site. Science, this issue p. 642 A repurposed drug-library screen reveals two allosteric drug binding sites of the SARS-CoV-2 main protease. The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.","publicationTypes":["JournalArticle"],"tldr":{"model":"tldr@v2.0.0","text":"A high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease, which is essential for viral replication, revealed two allosteric drug binding sites representing attractive targets for drug development against Sars-Cov-2."}},"tag":"DRUG"}]