Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(11), P. 7561 - 7580

Published: May 27, 2022

SARS-CoV-2 is the causative agent of COVID-19 pandemic. The approval vaccines and small-molecule antivirals vital in combating viral polymerase inhibitors remdesivir molnupiravir main protease inhibitor nirmatrelvir/ritonavir have been approved by U.S. FDA. However, emergence variants concern/interest calls for additional with novel mechanisms action. papain-like (PLpro) mediates cleavage polyprotein modulates host's innate immune response upon infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements structure-based design high-throughput screening PLpro since beginning Encouraging progress includes non-covalent favorable pharmacokinetic properties first-in-class covalent inhibitors. In addition, we offer our opinion on knowledge gaps that need to be filled advance clinic.

Language: Английский

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Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 13(2), P. 498 - 516

Published: Aug. 3, 2022

Peptide-drug conjugates (PDCs) are the next generation of targeted therapeutics drug after antibody-drug (ADCs), with core benefits enhanced cellular permeability and improved selectivity. Two drugs now approved for market by US Food Drug Administration (FDA), in last two years, pharmaceutical companies have been developing PDCs as therapeutic candidates cancer, coronavirus disease 2019 (COVID-19), metabolic diseases, so on. The significant, but poor stability, low bioactivity, long research development time, slow clinical process agents PDC, how can we design more effectively what is future direction PDCs? This review summarises components functions therapeutic, from target screening PDC improvement strategies to applications improve permeability, targeting, stability various PDCs. holds great promise PDCs, such bicyclic peptide‒toxin coupling or supramolecular nanostructures peptide-conjugated drugs. mode delivery determined according current trials summarised. way shown development.

Language: Английский

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Antiviral Drug Discovery for the Treatment of COVID-19 Infections

Viruses, Journal Year: 2022, Volume and Issue: 14(5), P. 961 - 961

Published: May 4, 2022

The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting vaccinated from infection, reducing severity of disease, and deterring transmission infection. However, vaccination faces many challenges, such as decline vaccine-induced immunity over time, decrease potency against some SARS-CoV-2 variants including Omicron variant, resulting breakthrough infections. challenges that facing highlight importance discovery antivirals serve another means tackle pandemic. To date, neutralizing antibodies block viral entry targeting spike protein make up largest class has received US FDA emergency use authorization (EUA) for treatment. In addition protein, other key targets direct-acting include enzymes are essential replication, RNA-dependent RNA polymerase proteases, judged approval remdesivir, EUA Paxlovid (nirmatrelvir + ritonavir) treating This review presents an overview current status future direction antiviral drug infections, covering important non-structural (nsp) 3 papain-like protease, nsp5 main nsp12/nsp7/nsp8 complex.

Language: Английский

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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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Peptide-Drug Conjugates: A New Hope for Cancer Management

Molecules, Journal Year: 2022, Volume and Issue: 27(21), P. 7232 - 7232

Published: Oct. 25, 2022

Cancer remains the leading cause of death worldwide despite advances in treatment options for patients. As such, safe and effective therapeutics are required. Short peptides provide advantages to be used cancer management due their unique properties, amazing versatility, progress biotechnology overcome peptide limitations. Several appealing peptide-based therapeutic strategies have been developed. Here, we an overview conjugates, better equivalents antibody-drug as next generation drugs required precise targeting, enhanced cellular permeability, improved drug selectivity, reduced toxicity efficient cancers. We discuss basic components conjugates release action, including cytotoxins from linker. also present peptide-drug under different stages clinical development well regulatory other challenges.

Language: Английский

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SARS‐CoV‐2 Papain‐Like Protease: Structure, Function and Inhibition

ChemBioChem, Journal Year: 2022, Volume and Issue: 23(19)

Published: Aug. 22, 2022

Abstract Emerging variants of SARS‐CoV‐2 and potential novel epidemic coronaviruses underline the importance investigating various viral proteins as drug targets. The papain‐like protease has been less explored than other proteins; however, its substantive role in replication impact on host immune response make it a suitable target to study. This review article focuses structure function (PL pro ) SARS‐CoV‐2, including concern, compares those coronaviruses, such SARS‐CoV‐1 MERS‐CoV. protease's recognition motif is mirrored ubiquitin ISG15, which are involved antiviral response. Inhibitors, GRL0617 derivatives, their prospects future agents also discussed.

Language: Английский

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Traceless Peptide and Protein Modification via Rational Tuning of Pyridiniums

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2624 - 2633

Published: Jan. 19, 2024

Herein, we report a versatile reaction platform for tracelessly cleavable cysteine-selective peptide/protein modification. This offers highly tunable and predictable conjugation cleavage by rationally estimating the electron effect on nucleophilic halopyridiniums. Cleavable peptide stapling, antibody conjugation, enzyme masking/de-masking, proteome labeling were achieved based this facile pyridinium-thiol-exchange protocol.

Language: Английский

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Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Aug. 11, 2022

SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of viral polypeptide chain, PLpro has additional and vital function removing ubiquitin ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading host's innate immune responses. We identified three phenolic compounds bound PLpro, preventing essential molecular interactions by screening a natural compound library. The X-ray complexed demonstrate clear inhibition deISGylation activity assay. Two exhibit distinct antiviral Vero cell line assays one inhibited cytopathic effect non-cytotoxic concentration ranges. In context increasing mutations evolving new variants SARS-CoV-2, we may also reinstate response processes host that are down-regulated COVID-19 infections.

Language: Английский

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Peptide‐based covalent inhibitors of protein–protein interactions

Journal of Peptide Science, Journal Year: 2022, Volume and Issue: 29(1)

Published: Oct. 14, 2022

Protein–protein interactions (PPI) are involved in all cellular processes and many represent attractive therapeutic targets. However, the frequently rather flat large interaction areas render identification of small molecular PPI inhibitors very challenging. As an alternative, peptide motifs derived from a interface can serve as starting points for development inhibitors. certain proteins remain challenging targets when applying with competitive mode action. For that reason, peptide‐based ligands irreversible binding have gained attention recent years. This review summarizes examples covalent employ peptidic binders been tested biological context.

Language: Английский

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Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal

Journal of Biomedical Science, Journal Year: 2022, Volume and Issue: 29(1)

Published: Sept. 6, 2022

Unprecedented efforts of the researchers have been witnessed in recent past towards development vaccine platforms for control COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing anti-COVID19 arsenal with therapeutic options such small molecules/peptides and antibodies is being conceived prudent tackle emerging variants. Noteworthy mention that collective from numerous teams led generation voluminous library composed chemically mechanistically diverse molecules scaffolds. This review article presents an overview medicinal chemistry campaigns drug repurposing programs culminated identification plethora molecule-based drugs mediating their antiviral effects through inhibition proteases, S protein, RdRp, ACE2, TMPRSS2, cathepsin other targets. In light evidence ascertaining potential molecule approach conserved proteins required viral replication all coronaviruses, accelerated FDA approvals are anticipated treatment COVID19 shortly. Though attempts invested this direction pursuit enrichment anti-COVID-19 armoury (chemical tools) praiseworthy, some strategies need be implemented extract conclusive benefits recently reported viz. (i) detailed preclinical investigation generated scaffolds (ii) in-vitro profiling inhibitors against variants (iii) assays enabling rapid screening libraries scaffold (iv) leveraging applications machine learning based predictive models expedite discovery campaign (v) design antibody-drug conjugates.

Language: Английский

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