Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(17), С. 14986 - 15011

Опубликована: Авг. 15, 2024

SARS-CoV-2 infections pose a high risk for vulnerable patients. In this study, we designed benzoic acid halopyridyl esters bearing variety of substituents as irreversible inhibitors the main viral protease (Mpro). Altogether, 55 benzoyl chloro/bromo-pyridyl were synthesized, with broad variation substitution pattern on moiety. A workflow was employed multiparametric optimization, including Mpro inhibition assays and related pathogenic coronaviruses, duration enzyme inhibition, compounds' stability versus glutathione, cytotoxicity, antiviral activity. Several compounds showed IC50 values in low nanomolar range, kinact/Ki >100,000 M–1 s–1 High-resolution X-ray cocrystal structures indicated an important role ortho-fluorobenzoyl substitution, forming water network that stabilizes inhibitor-bound enzyme. The most potent compound p-ethoxy-o-fluorobenzoyl chloropyridyl ester (PSB-21110, 29b, MW 296 g/mol; EC50 2.68 nM), which may serve lead structure broad-spectrum anticoronaviral therapeutics.

Язык: Английский

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Investigating the inhibition of benzimidazole derivatives on SARS-CoV-2 M ^pro by enzyme activity inhibition, spectroscopy, and molecular docking

Journal of Biomolecular Structure and Dynamics, Год журнала: 2025, Номер unknown, С. 1 - 16

Опубликована: Фев. 19, 2025

The inhibition of twenty-five 1,2-fused/disubstituted benzimidazoles on the SARS-CoV-2 Mpro were investigated in this work. It was found that four compounds (1i, 1k, 1l, and 1m) showed obvious inhibitory effect Mpro. 1k (IC50 46.86 μM) best. UV-vis, fluorescence, CD molecular docking methods used to reveal mechanisms interaction between these Results indicated static quenching main type quenching. 1i, 1m may alter conformation microenvironment dominant forces 1i (or 1l) hydrogen bonds or van der Waals forces. electrostatic hydrophobic forces, which consistent with results docking. influence structure binding investigated. Chlorine atom groups favorable for derivative inhibitors This work confirmed changes micro-environment by provided clues design potential inhibitors.

Язык: Английский

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Long COVID‐19 gastrointestinal related disorders and traditional Chinese medicine: A network target‐based approach

Phytotherapy Research, Год журнала: 2024, Номер 38(5), С. 2323 - 2346

Опубликована: Фев. 29, 2024

Abstract The significant number of individuals impacted by the pandemic makes prolonged symptoms after COVID‐19 a matter considerable concern. These are numerous and affect multiple organ systems. According to World Health Organization (WHO), gastrointestinal issues crucial part post‐COVID‐19 syndrome. resulting disruption homeostasis underscores need for therapeutic approach based on compounds that can simultaneously more than one target/node. present review aimed check nutraceuticals possessing molecular mechanisms helpful in relieving Long COVID‐19‐specific symptoms. Specific plants used Keywords Chinese Medicine (TCM) expected be included WHO Global Medical Compendium were selected following criteria: (1) they widely Western world as natural remedies complementary medicine adjuvants; (2) their import trade regulated specific laws ensure quality safety (3) have potential beneficial alleviating intestinal associated with COVID‐19. Searches performed PubMed, Elsevier, Google Scholar, Scopus, Science Direct, ResearchGate up 2023. Cinnamomum cassia , Glycyrrhiza uralensis Magnolia officinalis Poria cocos Salvia miltiorrhiza Scutellaria baicalensis Zingiber identified most promising impact inflammation oxidative stress. Based phytocomplexes isolated considered plants, clinical use may lead benefits diseases COVID‐19, thanks multiorgan multitarget approach.

Язык: Английский

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Recent Applications of Protoberberines as Privileged Starting Materials for the Development of Novel Broad-Spectrum Antiviral Agents: A Concise Review (2017–2023)

ACS Pharmacology & Translational Science, Год журнала: 2023, Номер 7(1), С. 48 - 71

Опубликована: Дек. 28, 2023

Berberine is a well-known phytochemical with significant antiviral activity against wide range of viruses. Due to having unique backbone consisting four interconnected rings, it can be used as platform for the design and development novel semisynthetic agents. The question here whether broad-spectrum drugs enhanced toxicity potential obtained by attempting modify structure this privileged lead compound. present study aims review results recent studies in which berberine its close analogues (protoberberine alkaloids) have been starting materials production new structures. For purpose, relevant published high-quality journals indexed databases such Scopus, Web Science, PubMed, etc. time frame 2017 2023 were collected. Our selection criterion current focuses on protoberberines agents during indicated period. Correspondingly, identified derivatives inhibitory viruses including human immunodeficiency virus (HIV), enterovirus 71 (EV71), zika (ZIKV), influenza A/B, cytomegalovirus (CMV), respiratory syncytial (RSV), coxsackieviruses designed synthesized. conclusion that, despite introduction diverse improved profiles compared parent natural leads, sufficient derivatization has not done yet more are needed.

Язык: Английский

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Effect and mechanism of quercetin or quercetin‐containing formulas against COVID‐19: From bench to bedside

Phytotherapy Research, Год журнала: 2024, Номер 38(6), С. 2597 - 2618

Опубликована: Март 13, 2024

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has caused the global disease 2019 (COVID‐19) pandemic since 2019. Immunopathogenesis and thromboembolic events are central to its pathogenesis. Quercetin exhibits several beneficial activities against COVID‐19, including antiviral, anti‐inflammatory, immunomodulatory, antioxidative, antithrombotic effects. Although reviews have been published, these incomplete from viewpoint of translational medicine. The authors comprehensively evaluated evidence quercetin both basically clinically, apply and/or derivatives in future. searched PubMed, Embase, Cochrane Library databases without any restrictions. search terms included SARS‐CoV‐2, quercetin, thrombosis, embolism, oxidative, microbiota. references relevant articles were also reviewed. All independently screened reviewed quality each manuscript. Risk Bias Tool, version (RoB 2) was used assess randomized controlled trials (RCTs). selected studies discussed monthly. effectiveness COVID‐19 is not solid due methodological flaws clinical trials. High‐quality required for quercetin‐containing traditional Chinese medicines. low bioavailability highly variable pharmacokinetics hinder applications. Its positive impact on immunomodulation through reverting dysbiosis gut microbiota still lacks robust evidence. does tough Strategies improve develop effective needed. Well‐designed RCTs crucial confirm their

Язык: Английский

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How many organic small molecules might be used to treat COVID-19? From natural products to synthetic agents

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 278, С. 116788 - 116788

Опубликована: Сен. 4, 2024

Язык: Английский

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Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Июль 2, 2024

Zoonotic coronaviruses are known to produce severe infections in humans and have been the cause of significant morbidity mortality worldwide. SARS-CoV-2 was largest latest contributor fatal cases, even though MERS-CoV has highest case-fatality ratio among zoonotic coronaviruses. These pose a high risk public health worldwide warranting efforts for expeditious discovery antivirals. Hence, we hereby describe novel series inhibitors coronavirus 3CLpro embodying an N-substituted 2-pyrrolidone scaffold envisaged exploit favorable interactions with S3–S4 subsites connected invariant Leu-Gln P2–P1 recognition element. Several showed nanomolar antiviral activity enzyme cell-based assays, no cytotoxicity. High-resolution crystal structures bound were determined probe identify molecular determinants associated binding, inform structure-guided optimization inhibitors, confirm mechanism action inhibitors.

Язык: Английский

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AI Promoted Virtual Screening, Structure-Based Hit Optimization, and Synthesis of Novel COVID-19 S-RBD Domain Inhibitors

Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 64(22), С. 8562 - 8585

Опубликована: Ноя. 13, 2024

Coronavirus disease 2019 (COVID-19) is caused by a new, highly pathogenic severe-acute-respiratory syndrome coronavirus 2 (SARS-CoV-2) that infects human cells through its transmembrane spike (S) glycoprotein. The receptor-binding domain (RBD) of the S protein interacts with angiotensin-converting enzyme II (ACE2) receptor host cells. Therefore, pharmacological targeting this interaction might prevent infection or spread virus. Here, we performed virtual screening to identify small molecules block S-ACE2 interaction. Large compound libraries were filtered for drug-like properties, promiscuity and protein-protein interaction-targeting ability based on their ADME-Tox descriptors also exclude pan-assay interfering compounds. A properly designed AI-based pipeline was applied remaining compounds, comprising approximately 10% starting data sets, searching could bind RBD protein. All sorted according score, grouped structure postfiltered possible patterns ACE2 receptor, yielding 31 hits. These hit further tested inhibitory effect Spike RBD/ACE2 (19-615) Six compounds inhibited in dose-dependent manner while two them prevented from pseudotyped virus whose entry mediated SARS-CoV-2. Of benzimidazole derivative

Язык: Английский

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The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity

Structure, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

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