Silaproline-bearing nirmatrelvir derivatives are potent inhibitors of the SARS-CoV-2 main protease highlighting the value of silicon-derivatives in structure-activity-relationship studies DOI Creative Commons

Dóra Laczi,

Sofia Schönbauer Huamán,

Taylah Andrews-Clark

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117603 - 117603

Опубликована: Апрель 1, 2025

Nirmatrelvir is a substrate-related inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro) that clinically used in combination with ritonavir to treat COVID-19. Derivatives nirmatrelvir, modified at substrate P2-equivalent position, have been developed fine-tune properties and are now clinical use. We report synthesis nirmatrelvir derivatives (R)-4,4-dimethyl-4-silaproline (silaproline) group position. Mass spectrometry (MS)-based assays demonstrate silaproline-bearing efficiently inhibit isolated recombinant Mpro, albeit reduced potency compared nirmatrelvir. Investigations SARS-CoV-2 infected VeroE6 cells reveal inhibitors CF3 P4-equivalent position viral progression, implying incorporating silicon atoms into Mpro can yield vivo active appropriate optimization. MS crystallographic studies show nucleophilic site cysteine residue (Cys145) reacts nitrile inhibitors. Substituting electrophilic for non-activated terminal alkyne shifts inhibition mode from reversible covalent irreversible inhibition. One two prochiral silaproline methyl groups occupies space S2 pocket unoccupied Mpro:nirmatrelvir complex structures, highlighting value sila-derivatives structure-activity-relationship (SAR) studies. The combined results highlight potential silicon-containing molecules and, by implication, other enzymes.

Язык: Английский

Protein tyrosine phosphatase 4A3 inhibition: A new pharmacological strategy for acute lung injury? DOI
Paolo Montuschi, Ian M. Adcock

Journal of Pharmacology and Experimental Therapeutics, Год журнала: 2025, Номер 392(3), С. 100045 - 100045

Опубликована: Янв. 10, 2025

Язык: Английский

Процитировано

0
Research Progress on the Structure and Function, Immune Escape Mechanism, Antiviral Drug Development Methods, and Clinical Use of SARS-CoV-2 Mpro DOI Creative Commons
Jiayi Ren, Zhengfu Zhang, Yi Xia

и другие.

Molecules, Год журнала: 2025, Номер 30(2), С. 351 - 351

Опубликована: Янв. 16, 2025

The three-year COVID-19 pandemic ‘has’ caused a wide range of medical, social, political, and financial implications. Since the end 2020, various mutations variations in SARS-CoV-2 strains, along with immune escape phenomenon, have emerged. There is an urgent need to identify relatively stable target for development universal vaccines drugs that can effectively combat both strains their mutants. Currently, main focus treating lies disrupting virus’s life cycle. protease (Mpro) closely associated virus replication maturation plays crucial role early stages infection. Consequently, it has become important SARS-CoV-2-specific drugs. This review summarizes recent research progress on novel coronavirus’s proteases, including pivotal Mpro cycle, structure catalytic mechanism Mpro, self-maturation escape, current methods developing antiviral targeting key successfully entered clinical trials. aim provide researchers involved systematic comprehensive information.

Язык: Английский

Процитировано

0
In Silico Discovery of SARS-CoV-2 Main Protease Inhibitors Using Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations DOI
Takeshi Ishikawa, Kenji Matsumoto, Toshiyuki Hamada

и другие.

The Journal of Physical Chemistry B, Год журнала: 2025, Номер 129(6), С. 1740 - 1749

Опубликована: Янв. 31, 2025

The 3C-like protease of severe acute respiratory syndrome coronavirus 2, known as the main (Mpro), is an attractive drug target for treatment disease 2019. This study reports discovery novel Mpro inhibitors using several in silico techniques, including docking, molecular dynamics (MD), and fragment orbital (FMO) calculations. We performed docking calculations on 5950 compounds with bioactivity, 12 were selected. An enzymatic assay was conducted, revealing that BP-1-102 exhibits significant inhibitory activity IC50 11.1 μM. identification seed from experiments a few demonstrates effectiveness our Furthermore, detailed analyses MD FMO suggested interaction mechanism which hydroxyl group forms hydrogen bond E166 Mpro. SH-4-54, derivative without aforementioned group, investigated observed to be significantly reduced, 81.5 result strongly supports mechanism.

Язык: Английский

Процитировано

0
Discovery of The Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19 DOI Open Access
Yuto Unoh,

Keiichiro Hirai,

Shota Uehara

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 28, 2025

Abstract The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health an unmet need for options. Herein, we report the discovery of S-892216 , a second-generation SARS-CoV-2 3C-like protease (3CL pro ) inhibitor, treat COVID-19. is reversible covalent 3CL inhibitor with highly potent antiviral activity EC 50 value 2.48 nM against infected cells. Structure-based design modifier compound 1 revealed that introducing nitrile warhead increased inhibition 180-fold. Subsequent optimization yielded which combined favorable pharmacokinetic profile high off-target selectivity. exhibited diverse variants, no cross-resistance major mutations reducing activities nirmatrelvir ensitrelvir. In SARS-CoV-2-infected mice, inhibited viral replication in lungs similar ensitrelvir, although at 30-fold lower dose.

Язык: Английский

Процитировано

0
A Reflection on the Use of Molecular Simulation to Respond to SARS-CoV-2 Pandemic Threats DOI Creative Commons
Lorenzo Casalino, Carlos A. Ramos‐Guzmán, Rommie E. Amaro

и другие.

The Journal of Physical Chemistry Letters, Год журнала: 2025, Номер unknown, С. 3249 - 3263

Опубликована: Март 21, 2025

Molecular simulations play important roles in understanding the lifecycle of SARS-CoV-2 virus and contribute to design development antiviral agents diagnostic tests for COVID. Here, we discuss insights that such have provided challenges involved, focusing on main protease (Mpro) spike glycoprotein. Mpro is leading target antivirals, while glycoprotein vaccine design. Finally, reflect lessons from this pandemic simulation community. Data sharing initiatives collaborations across international research community contributed advancing knowledge should be built help future pandemics other global as antimicrobial resistance.

Язык: Английский

Процитировано

0
Silaproline-bearing nirmatrelvir derivatives are potent inhibitors of the SARS-CoV-2 main protease highlighting the value of silicon-derivatives in structure-activity-relationship studies DOI Creative Commons

Dóra Laczi,

Sofia Schönbauer Huamán,

Taylah Andrews-Clark

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117603 - 117603

Опубликована: Апрель 1, 2025

Nirmatrelvir is a substrate-related inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro) that clinically used in combination with ritonavir to treat COVID-19. Derivatives nirmatrelvir, modified at substrate P2-equivalent position, have been developed fine-tune properties and are now clinical use. We report synthesis nirmatrelvir derivatives (R)-4,4-dimethyl-4-silaproline (silaproline) group position. Mass spectrometry (MS)-based assays demonstrate silaproline-bearing efficiently inhibit isolated recombinant Mpro, albeit reduced potency compared nirmatrelvir. Investigations SARS-CoV-2 infected VeroE6 cells reveal inhibitors CF3 P4-equivalent position viral progression, implying incorporating silicon atoms into Mpro can yield vivo active appropriate optimization. MS crystallographic studies show nucleophilic site cysteine residue (Cys145) reacts nitrile inhibitors. Substituting electrophilic for non-activated terminal alkyne shifts inhibition mode from reversible covalent irreversible inhibition. One two prochiral silaproline methyl groups occupies space S2 pocket unoccupied Mpro:nirmatrelvir complex structures, highlighting value sila-derivatives structure-activity-relationship (SAR) studies. The combined results highlight potential silicon-containing molecules and, by implication, other enzymes.

Язык: Английский

Процитировано

0