Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(19), P. 12500 - 12534

Published: Sept. 28, 2022

The viral main protease is one of the most attractive targets among all key enzymes involved in SARS-CoV-2 life cycle. Covalent inhibition cysteine145 MPRO with selective antiviral drugs will arrest replication process virus without affecting human catalytic pathways. In this Perspective, we analyzed silico, vitro, and vivo data representative examples covalent inhibitors reported literature to date. particular, studied molecules were classified into eight different categories according their reactive electrophilic warheads, highlighting differences between reversible/irreversible mechanism inhibition. Furthermore, analyses recurrent pharmacophoric moieties stereochemistry chiral carbons reported. noncovalent silico protocols, provided would be useful for scientific community discover new more efficient inhibitors.

Language: Английский

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Recent Advances in Covalent Drug Discovery

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(5), P. 663 - 663

Published: April 28, 2023

In spite of the increasing number biologics license applications, development covalent inhibitors is still a growing field within drug discovery. The successful approval some protein kinase inhibitors, such as ibrutinib (BTK inhibitor) and dacomitinib (EGFR inhibitor), very recent discovery for viral proteases, boceprevir, narlaprevir, nirmatrelvir, represent new milestone in development. Generally, formation bonds that target proteins can offer drugs diverse advantages terms selectivity, resistance, administration concentration. most important factor electrophile (warhead), which dictates reactivity, type binding (i.e., reversible or irreversible) be modified/optimized through rational designs. Furthermore, are becoming more common proteolysis, targeting chimeras (PROTACs) degrading proteins, including those currently considered to ‘undruggable’. aim this review highlight current state inhibitor development, short historical overview examples applications PROTAC technologies treatment SARS-CoV-2 virus.

Language: Английский

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A Comprehensive Guide for Assessing Covalent Inhibition in Enzymatic Assays Illustrated with Kinetic Simulations

Current Protocols, Journal Year: 2022, Volume and Issue: 2(6)

Published: June 1, 2022

Covalent inhibition has become more accepted in the past two decades, as illustrated by clinical approval of several irreversible inhibitors designed to covalently modify their target. Elucidation structure-activity relationship and potency such requires a detailed kinetic evaluation. Here, we elucidate between experimental read-out underlying inhibitor binding kinetics. Interactive simulation scripts are employed highlight effects vitro enzyme activity assay conditions mode, thereby showcasing which assumptions corrections crucial. Four stepwise protocols assess biochemical (ir)reversible covalent targeting nucleophilic active site residue included, with accompanying data analysis tailored mode. Together, this will serve guide make an educated decision regarding most suitable method potency. © 2022 The Authors. Current Protocols published Wiley Periodicals LLC. Basic Protocol I: Progress curve substrate association competition Data Analysis 1A: Two-step 1B: One-step 1C: reversible 1D: depletion II: Incubation time-dependent IC50 (t) 2: III: Preincubation without dilution 3: 3Ai: Alternative 3Aii: 3Bi: 3Bii: 3C: IV: dilution/competition 4: 4Ai: 4Aii: 4Bi: 4Bii: inhibition.

Language: Английский

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New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

Chemistry - A European Journal, Journal Year: 2022, Volume and Issue: 28(56)

Published: July 5, 2022

Extension of the medicinal chemistry toolbox is in vital interest drug designers. However, diffusion an innovation can be a lengthy process. Along these lines, it took almost 70 years before use sulfoximine group reached critical mass chemistry. Even though this versatile functional has increased exponentially recent years, there ample room for further innovative applications. This Review highlights emerging trends and opportunities designers utilization chemistry, such as construction complex molecules, proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) novel warheads covalent inhibition.

Language: Английский

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Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development

Molecules, Journal Year: 2022, Volume and Issue: 27(22), P. 7728 - 7728

Published: Nov. 10, 2022

Cysteine is one of the least abundant amino acids in proteins many organisms, which plays a crucial role catalysis, signal transduction, and redox regulation gene expression. The thiol group cysteine possesses ability to perform nucleophilic redox-active functions that are not feasible for other natural acids. most common covalent acid residue has been shown react with variety warheads, especially Michael receptors. These unique properties have led widespread interest this nucleophile, leading development cysteine-targeting warheads different chemical compositions. Herein, we summarized various targeting their application drug development.

Language: Английский

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The expanding repertoire of covalent warheads for drug discovery

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103799 - 103799

Published: Oct. 13, 2023

Language: Английский

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Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 797 - 797

Published: July 4, 2024

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.

Language: Английский

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Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

The discovery of elironrasib (RMC-6291) represents a significant breakthrough in targeting the previously deemed undruggable GTP-bound, active KRASG12C. To target state RAS (RAS(ON)) directly, we have employed an innovative tri-complex inhibitor (TCI) modality involving formation complex with inhibitor, intracellular chaperone protein CypA, and KRASG12C its GTP-bound form. resulting inhibits oncogenic signaling, inducing tumor regressions across various preclinical models mutant human cancers. Here report structure-guided medicinal chemistry efforts that led to elironrasib, potent, orally bioavailable, RAS(ON) G12C-selective, covalent, inhibitor. investigational agent is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), preliminary data indicating activity patients who had progressed on first-generation inactive state-selective inhibitors.

Language: Английский

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Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases

Molecules, Journal Year: 2022, Volume and Issue: 27(8), P. 2561 - 2561

Published: April 15, 2022

In the field of drug discovery, nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent covalent interactions with diverse biological targets, it amenable as an electrophilic warhead for inhibition. The main advantage a mainly due to its milder character relative other more reactive groups (e.g., -CHO), reducing possibility unwanted reactions that would hinder development safe drugs, coupled ease installation through different synthetic approaches. inhibition well-assessed design approach serine, threonine, cysteine protease inhibitors. mechanism hydrolysis these enzymes involves formation acyl intermediate, this be exploited by introducing warheads in order mimic intermediate. Due relevant role played survival replication infective agents, spanning from viruses protozoan parasites, we will review most recent examples inhibitors presenting have been introduced or facilitate bond catalytic site residue.

Language: Английский

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Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(4), P. 824 - 838

Published: April 3, 2024

Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading covalent adducts, there been success developing inhibitors, especially within field anticancer therapy. inhibitors can have an advantage over noncovalent since formation adduct may serve as additional mode selectivity intrinsic reactivity target protein that is absent many other proteins. Unfortunately, form irreversible adducts with proteins, which lead considerable side-effects. By designing inhibitor reversible one leverage competing on/off kinetics complex taking law mass action. do nature prevents accumulation adduct, thus limiting In this perspective, we outline important characteristics including examples and guide for development.

Language: Английский

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