Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107380 - 107380

Published: April 16, 2024

Language: Английский

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Myocardial Oedema as a Consequence of Viral Infection and Persistence—A Narrative Review with Focus on COVID-19 and Post COVID Sequelae

Viruses, Journal Year: 2024, Volume and Issue: 16(1), P. 121 - 121

Published: Jan. 14, 2024

Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic removal disturbed during pathological processes leading to inflammation, but also hypoxia or due alterations vascular perfusion coagulability. degradation of the glycocalyx as main component endothelial barrier well pericyte disintegration results accumulation interstitial intracellular water. Moreover, dysfunction evokes an increase metabolic waste products, cytokines inflammatory cells space contributing oedema formation. This leads stiffness impaired contractility, eventually resulting cardiomyocyte apoptosis, remodelling fibrosis. following article reviews pathophysiological including myocarditis, ischaemia-reperfusion injury viral infections with special focus on pathomechanisms evoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, clinical implications potential long-term effects persistence (long COVID), treatment options, are discussed.

Language: Английский

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Computer-aided drug design of novel nirmatrelvir analogs inhibiting main protease of Coronavirus SARS-CoV-2

Journal of Applied Pharmaceutical Science, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

A computer-aided drug design of new derivatives nirmatrelvir, an orally active inhibitor the main-protease (Mpro) severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), was performed to identify its analogues with a higher antiviral potency. The following workflow used: first, evolutionary library composed 1,866 generated starting from parent nirmatrelvir scaffold and going through small mutation, fitness scoring, ranking, selection. Second, preprocessed filtered against 3-D pharmacophore model built X-ray structure in co-crystalized complex Mpro enzyme, allowing us reduce chemical space 32 analogues. Third, structure-based molecular docking two different enzyme structures further ranked these candidates, so that up eight better-binding analogs were identified. selected hit-analogues target enzymes SARS-CoV-2 binding affinity than nirmatrelvir. main structural modifications increase overall inhibitory are identified at azabicyclo[3.1.0] hexane 2-oxopyrrolidine fragments. characteristic feature centre is similar location trifluoroacetylamino fragment, which observed for most hit-analogues. suggested rational noncovalent inhibitors based on approved drugs promising, extremely low-cost, time-efficient approach development potential pharmaceutical ingredients treatment Disease 2019.

Language: Английский

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Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (M^pro)

ACS Omega, Journal Year: 2024, Volume and Issue: 9(32), P. 34196 - 34219

Published: Aug. 2, 2024

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), by SARS-CoV-2 its variants, further highlighted urgent need for development effective therapeutic agents. Currently, highly conserved broad-spectrum nature main proteases (M

Language: Английский

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3-Chymotrypsin-like Protease (3CLpro) of SARS-CoV-2: Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

Viruses, Journal Year: 2024, Volume and Issue: 16(6), P. 844 - 844

Published: May 24, 2024

Proteases represent common targets in combating infectious diseases, including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19, and it key developing potent selective inhibitors inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships diverse subsites 3CLpro, shedding light on the pivotal role dimerization active site architecture substrate recognition catalysis. Our analysis bioinformatics other published studies motivated us to investigate novel catalytic mechanism SARS-CoV-2 polyprotein cleavage by centering triad involving His41-Cys145-Asp187 its indispensable replication. hypothesis that Asp187 may participate modulating pKa His41, which histidine act as an acid and/or base mechanism. Recognizing crucial component process underscores significance fundamental pharmacophoric element drug design. Next, provide overview both covalent non-covalent inhibitors, elucidating advancements development observed preclinical clinical trials. By highlighting various chemical classes their pharmacokinetic profiles, our review aims guide future research directions toward highly underscore 3CLpro therapeutic target, propel progression candidates through phases.

Language: Английский

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Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CL^pro Inhibitors as anti-SARS-CoV-2 Drug Candidate

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(15), P. 12760 - 12783

Published: July 29, 2024

SARS-CoV-2 has still been threatening global public health with its emerging variants. Our previous work reported lead compound JZD-07 that displayed good 3CLpro inhibitory activity. Here, an in-depth structural optimization for was launched to obtain more desirable drug candidates the therapy of infection, in which 54 novel derivatives were designed and synthesized by a structure-based design strategy. Among them, 24 compounds show significantly enhanced potencies IC50 values less than 100 nM, 11 dose-dependently inhibit replication delta variant. In particular, 49 most antiviral activity EC50 0.272 ± 0.013 μM against variant, 20 times stronger JZD-07. Oral administration could reduce lung viral copies mice, exhibiting favorable therapeutic potential. Overall, this investigation presents promising candidate further development treat infection.

Language: Английский

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Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 12266 - 12283

Published: Aug. 18, 2023

3CLpro is an attractive target for the treatment of COVID-19. Using scaffold hopping strategy, we identified a potent inhibitor (3a) that contains thiocyanate moiety as novel warhead can form covalent bond with Cys145 protein. Tandem mass spectrometry (MS/MS) and X-ray crystallography confirmed mechanism formation between 3a protein in its catalytic pocket. Moreover, several analogues compound were designed synthesized. Among them, 3h shows best inhibition IC50 0.322 μM kinact/Ki value 1669.34 M–1 s–1, it exhibits good selectivity against host proteases. Compound 3c inhibits SARS-CoV-2 Vero E6 cells (EC50 = 2.499 μM) low cytotoxicity (CC50 > 200 μM). These studies provide ideas insights to explore develop new inhibitors future.

Language: Английский

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DNA-Compatible Cyclization Reaction to Access 1,3,4-Oxadiazoles and 1,2,4-Triazoles

Organic Letters, Journal Year: 2024, Volume and Issue: 26(7), P. 1353 - 1357

Published: Feb. 9, 2024

DNA-encoded chemical library (DECL) technology is a commonly employed screening platform in both the pharmaceutical industry and academia. To expand space of DECLs, new robust DNA-compatible reactions are sought after. In particular, cyclization highly valued, as these tend to be atom economical thus may provide lead- drug-like molecules. Herein, we report two methodologies employing DNA-conjugated thiosemicarbazides common precursor, yielding substituted 1,3,4-oxadiazoles 1,2,4-triazoles. These novel feature high conversion efficiency broad substrate scope under mild conditions that do not observably degrade DNA.

Language: Английский

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Insilico generation of novel ligands for the inhibition of SARS-CoV-2 main protease (3CLpro) using deep learning

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: June 23, 2023

The recent emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the disease (COVID-19) has become a global public health crisis, and crucial need exists for rapid identification development therapeutic interventions. In this study, recurrent neural network (RNN) is trained optimized to produce ligands that could serve as potential inhibitors SARS-CoV-2 viral protease: 3 chymotrypsin-like protease (3CL pro ). Structure-based virtual screening was performed through molecular docking, ADMET profiling, predictions various properties were done evaluate toxicity drug-likeness generated ligands. also compared with current drugs under phases clinical trials assess efficacy Twenty selected exhibited good properties, most conforming Lipinski’s rule 5, high binding affinity (highest affinity: −9.4 kcal/mol), promising profile. Additionally, complexed 3CL found be stable based on results dynamics simulation studies conducted over 100 ns period. Overall, findings offer avenue effective interventions treat COVID-19.

Language: Английский

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A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants

Emerging Microbes & Infections, Journal Year: 2023, Volume and Issue: 12(2)

Published: Aug. 9, 2023

Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well emerging drug-resistant variants. We developed and characterized a novel class active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2-C5a). Our lead direct-acting antiviral (DAA), C5a, is non-covalent, non-peptide dissociation constant 170 nM against recombinant 3CLpro. The compounds C2-C5a exhibit broad-spectrum Omicron subvariants (BA.5, BQ.1.1, XBB.1.5) seasonal human coronavirus-229E infection in cells. Notably, C5a has median effective concentrations 30 – 50 BQ.1.1 XBB.1.5 two different cell lines. X-ray crystallography confirmed unique binding modes 3CLpro, which can limit virus cross-resistance Paxlovid-resistant tested effect our newly discovered host-directed antivirals (HDAs): N-0385, TMPRSS2 inhibitor, bafilomycin D (BafD), vacuolar H+-ATPase [V-ATPase] inhibitor. demonstrated synergistic action combination N-0385 BafD BA.5 Calu-3 lung findings underscore that multi-targeted treatment circulating based on DAAs (C5a) HDAs (N-0385 or BafD) therapeutic benefits by enhancing efficacy. Furthermore, high-resolution structures 3CLpro complex will facilitate future rational optimization 3C-like inhibitors.

Language: Английский

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