Advances in the Development of SARS-CoV-2 Mpro Inhibitors

Molecules, Journal Year: 2022, Volume and Issue: 27(8), P. 2523 - 2523

Published: April 14, 2022

Since the outbreak of COVID-19, one strategies used to search for new drugs has been find inhibitors main protease (Mpro) virus SARS-CoV-2. Initially, previously reported related proteases such as SARS-CoV and MERS-CoV were tested. A huge effort was then carried out by scientific community design, synthesize test small molecules acting inactivators SARS-CoV-2 Mpro. From chemical structure view, these compounds can be classified into two groups: corresponds modified peptides displaying an adequate sequence high affinity a reactive warhead; second is diverse group including that do not have peptide framework. Although drug inhibitor already commercialized, denoting importance this field, more demonstrated promising potent potential antiviral drugs.

Language: Английский

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Small-Molecule Ebselen Binds to YTHDF Proteins Interfering with the Recognition of N⁶-Methyladenosine-Modified RNAs

ACS Pharmacology & Translational Science, Journal Year: 2022, Volume and Issue: 5(10), P. 872 - 891

Published: Sept. 14, 2022

YTHDF proteins bind the N6-methyladenosine (m6A)-modified mRNAs, influencing their processing, stability, and translation. Therefore, members of this protein family play crucial roles in gene regulation several physiological pathophysiological conditions. contain a hydrophobic pocket that accommodates m6A embedded RRACH consensus sequence on mRNAs. We exploited presence cage to set up an m6A-competitive assay performed high-throughput screen aimed at identifying ligands binding pocket. report organoselenium compound ebselen as first-in-class inhibitor m6A-binding domain. Ebselen, whose interaction with was validated via orthogonal assays, cannot discriminate between domains three paralogs but can disrupt domain m6A-decorated mRNA targets. X-ray, mass spectrometry, NMR studies indicate YTHDF1 binds close cage, covalently Cys412 cysteine, or interacts reversibly depending reducing environment. also showed engages within cells, interfering binding. Finally, we produced series structural analogs interact domain, proving expansion is amenable for developing new inhibitors. Our work demonstrates feasibility drugging YTH opens avenues development disruptors recognition.

Language: Английский

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Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives

Biomolecules, Journal Year: 2023, Volume and Issue: 13(9), P. 1339 - 1339

Published: Sept. 2, 2023

The main protease (Mpro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered highly conserved viral target. Disruption catalytic activity Mpro produces detrimental effect on course infection, making this target one most attractive for treatment COVID-19. current success SARS-CoV-2 inhibitor Nirmatrelvir, first oral drug forms COVID-19, has further focused attention researchers important target, search new inhibitors thriving exciting field development antiviral drugs active against related coronaviruses.

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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SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

Future Pharmacology, Journal Year: 2023, Volume and Issue: 3(1), P. 80 - 107

Published: Jan. 9, 2023

While the COVID-19 pandemic seems to be on its decline, unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not underestimated threat. These along with preparedness, ask for an alert identification new drugs optimization existing as therapeutic treatment options this potential future diseases. Mpro inhibitors were identified early potent drug candidates against coronaviruses, since they target viable processing machinery within virus, i.e., main protease that cleaves polyproteins encoded by viral RNA into functional proteins. Different strategies, including reversible irreversible inhibition well allosteric inhibitors, mostly from repurposing endeavors, have been explored design SARS-CoV-2 antivirals. Ambitious screening efforts uttered outstanding chemical structural diversity, which has led half dozen lead compounds being currently clinical trials emergency FDA approval ritonavir-boosted nirmatrelvir therapeutic. This comprehensive analysis achieved inhibitor diversity sorted irreversible, reversible, binders, discussion emerging resistance reports possible evasion is aimed at stimulating continuing efforts.

Language: Английский

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