Inhibitors of SARS-CoV-2 PLpro

Frontiers in Chemistry, Journal Year: 2022, Volume and Issue: 10

Published: April 26, 2022

The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers hospitalized patients. antiviral treatments hence remains top priority preventing hospitalization death patients, eventually bringing an end pandemic. proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus nsp3, that harbours papain-like protease (PLpro) domain responsible for cleaving viral polyprotein as part processing. Moreover, nsp3/PLpro also cleaves ubiquitin ISG15 modifications host cell, derailing innate immune responses. Small molecule inhibition PLpro significantly reduces loads infection models, suggesting is excellent drug target next generation antivirals. In this review we discuss conserved structure function ongoing efforts design small inhibitors exploit knowledge. first many repurposing attempts, concluding it unlikely PLpro-targeting drugs already exist. wealth structural information inhibition, which there are now ∼30 distinct crystal structures bound surprising number crystallographic settings. optimisation compound class, based SARS-CoV inhibitor GRL-0617, recapitulate new GRL-0617 derivatives different features PLpro, overcome some liabilities.

Language: Английский

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Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(7), P. 3507 - 3507

Published: March 23, 2022

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of most devastating pandemics recent times. The lack potent novel antivirals had led to global health crises; however, emergence and approval inhibitors viral main protease (Mpro), such as Pfizer’s newly approved nirmatrelvir, offers hope not only in therapeutic front but also context prophylaxis against infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, lessons learnt from previous currently ongoing taught us that these can easily escape selection pressure through vital target amino acid residues monotherapeutic settings. In this paper, we review nirmatrelvir its binding SARS-CoV-2 Mpro draw a comparison HIV were rendered obsolete resistance mutations, emphasizing potential pitfalls design may be important relevance long-term use SARS-CoV-2.

Language: Английский

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Molnupiravir: A lethal mutagenic drug against rapidly mutating severe acute respiratory syndrome coronavirus 2—A narrative review

Journal of Medical Virology, Journal Year: 2022, Volume and Issue: 94(7), P. 3006 - 3016

Published: March 22, 2022

Broad-spectrum antiviral agents targeting viral RNA-dependent RNA polymerase (RdRp) are expected to be a key therapeutic strategy in the ongoing coronavirus disease 2019 (COVID-19) pandemic and its future variants of severe acute respiratory syndrome 2 (SARS-CoV-2), virus that causes COVID-19. Molnupiravir is nucleoside analog vivo experiments have been reported inhibit replication SARS-CoV-2, Clinical trials molnupiravir as therapy for patients with mild-to-moderate COVID-19 also suggest significant efficacy comparison placebo. lethally mutagenic against RNA, but effect on host cell DNA being questioned. Herein, safety concerns discussed recent findings from published reports clinical trials. The unchanged mutated SARS-CoV-2 highlighted. With administration via oral route, turn tide pandemic.

Language: Английский

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Emergence of SARS-CoV-2 Variants in the World: How Could This Happen?

Life, Journal Year: 2022, Volume and Issue: 12(2), P. 194 - 194

Published: Jan. 28, 2022

The COVID-19 pandemic has had a significant global impact, with more than 280,000,000 people infected and 5,400,000 deaths. use of personal protective equipment the anti-SARS-CoV-2 vaccination campaigns have reduced infection death rates worldwide. However, recent increase in been observed associated appearance SARS-CoV-2 variants, including recently described lineage B.1.617.2 (Delta variant) B.1.1.529/BA.1 (Omicron variant). These new variants put effectiveness international at risk, outbreaks throughout world. This emergence due to multiple predisposing factors, molecular characteristics virus, geographic environmental conditions, impact social determinants health that favor genetic diversification SARS-CoV-2. We present literature review on most information available analyzed biological, geographical, sociocultural factors development these variants. Finally, we evaluate surveillance strategies for early detection prevent their distribution outside regions.

Language: Английский

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Development of Metal Complexes for Treatment of Coronaviruses

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(12), P. 6418 - 6418

Published: June 8, 2022

Coronavirus disease (SARS-CoV-2) is a global epidemic. This pandemic, which has been linked to high rates of death, forced some countries throughout the world implement complete lockdowns in order contain spread infection. Because advent new coronavirus variants, it critical find effective treatments and vaccines prevent virus’s rapid over world. In this regard, metal complexes have attained immense interest as antibody modifiers antiviral therapies, they lot promise towards SARS-CoV-2 their suggested mechanisms action are discussed, i.e., series complexes’ medicinal vital role treatment specific proteins or described. The structures obtained were fully elucidated by different analytical spectroscopic techniques also. Molecular docking pharmacophore studies presented that most studied influenced good binding affinity main protease SARS-CoV-2, also was from RCSB pdb (Protein Data Bank) data PDB ID: 6 W41, expect contradiction COVID-19. Experimental research required determine pharmacokinetics analyzed for SARS-CoV-2-related disease. Finally, toxicity metal-containing inorganic complex will thus be discussed its capability transfer metals may bind with targeted site.

Language: Английский

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Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 7, 2023

Abstract The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden our society. Most patients infected are asymptomatic or have mild symptoms. Although only small proportion of progressed severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, cardiovascular disorders, is accompanied mortality rates near 7 million deaths. Nowadays, effective therapeutic patterns for still lacking. It been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate avoid immunity, facilitate their own replication, initiate pathological response. Targeting interaction between holds promise developing strategies. In this review, we summarize discuss recent studies dedicated uncovering role life cycle aspects entry, assembly, pathogenesis an emphasis on glucose lipid metabolism. Microbiota long also discussed. Ultimately, recapitulate metabolism-modulating drugs repurposed statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, metformin.

Language: Английский

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Immune evasion of neutralizing antibodies by SARS-CoV-2 Omicron

Cytokine & Growth Factor Reviews, Journal Year: 2023, Volume and Issue: 70, P. 13 - 25

Published: March 5, 2023

Language: Английский

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SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4834 - 4850.e23

Published: Oct. 1, 2023

Regulation of viral RNA biogenesis is fundamental to productive SARS-CoV-2 infection. To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified bound genomic and subgenomic RNAs. We find that the protein SND1 binds 5' end negative-sense required for synthesis. SND1-depleted cells form smaller replication organelles display diminished virus growth kinetics. discover NSP9, a RBP direct interaction partner, covalently linked ends positive- RNAs produced during These linkages occur at replication-transcription initiation sites, consistent with NSP9 priming Mechanistically, remodels occupancy alters covalent linkage initiating nucleotides RNA. Our findings implicate synthesis unravel an unsuspected role cellular orchestrating production.

Language: Английский

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Green and efficient one-pot three-component synthesis of novel drug-like furo[2,3-d]pyrimidines as potential active site inhibitors and putative allosteric hotspots modulators of both SARS-CoV-2 MPro and PLPro

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 135, P. 106390 - 106390

Published: Jan. 28, 2023

Language: Английский

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Ebselen derivatives inhibit SARS-CoV-2 replication by inhibition of its essential proteins: PLpro and Mpro proteases, and nsp14 guanine N7-methyltransferase

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: June 6, 2023

Abstract Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. main protease (M pro , 3CL ) and papain-like (PL are responsible viral polyprotein cleavage—a process crucial survival replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2 H )-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is potent, covalent inhibitor of both the proteases its potency evaluated in enzymatic antiviral assays. In this study, we screened collection 34 ebselen diselenide derivatives PL M inhibitors. Our studies revealed potent inhibitors proteases. We identified three four superior to ebselen. Independently, inhibit N7-methyltransferase activity nsp14 protein involved RNA cap modification. Hence, selected compounds were also as second part our work, employed 11 analogues—bis(2-carbamoylaryl)phenyl diselenides—in biological assays evaluate their anti-SARS-CoV-2 Vero E6 cells. present cytoprotective low cytotoxicity. work shows ebselen, derivatives, analogues platform development antivirals targeting virus.

Language: Английский

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