作者: Wang, Ruyu ; Zhu, Tong ; Chen, Lili ; Liu, Shunying ; Xu, Jianrong ; Lu, Jiani ; Chen, Xixiang ; Xue, Jian ; Deng, Yaqi ; Wang, Meiting ; Li, Yexi ; Song, Yuheng ; Li, Hongtao

Although the coronavirus disease 2019 (COVID-19) crisis has passed, there remains a necessity for continuous efforts toward developing more targeted drugs and preparing for potential future virus attacks. Currently, most of the drugs received authorization for the treatment of COVID-19 have exhibited several limitations, such as poor metabolic stability, formidable preparation, and uncertain effectiveness. It is still significant to develop novel, structurally diverse small-molecule antiviral drugs targeting SARS-CoV-2 3-chymotrypsin-like protease (3CL^pro). Herein, we report a class of alkynylamide-based nonpeptidic 3CL^pro inhibitors that can be prepared conveniently by our previously developed one-pot synthetic method. The structure-activity relationships of alkynylamides as SARS-CoV-2 3CL^pro inhibitors have been carefully investigated and discussed in this study. The two stereoisomers of the resulting molecules exhibit stereoselective interaction with 3CL^pro, and the optimized compound (S,R)-4y inhibits 3CL^pro with high potency (IC₅₀ = 0.43 μM), low cytotoxicity, and acceptable cell permeability. Compound (S,R)-4y presents as a noncovalent inhibitor of 3CL^pro against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. The Lineweaver-Burk plots, binding energy, surface plasmon resonance, and molecular docking studies suggest that (S,R)-4y specifically binds to an allosteric pocket of the SARS-CoV-2 3CL^pro. These findings provide a novel class of nonpeptidic alkynylamide-based allosteric inhibitors with high selectivity against SARS-CoV-2 3CL^pro featured by a simplified one-pot synthesis at room temperature in air.

2024-10-01·Inflammopharmacology

Taming the storm: potential anti-inflammatory compounds targeting SARS-CoV-2 MPro

Review

作者: Timmers, Luis Fernando Saraiva Macedo ; de Lima, Jeferson Camargo ; Goettert, Marcia Inês ; Dahmer, Bruno Rampanelli ; Camini, Ana Micaela ; Anton, Débora Bublitz

In severe COVID-19 cases, an exacerbated inflammatory response triggers a cytokine storm that can worsen the prognosis. Compounds with both antiviral and anti-inflammatory activities show promise as candidates for COVID-19 therapy, as they potentially act against the SARS-CoV-2 infection regardless of the disease stage. One of the most attractive drug targets among coronaviruses is the main protease (MPro). This enzyme is crucial for cleaving polyproteins into non-structural proteins required for viral replication. The aim of this review was to identify SARS-CoV-2 MPro inhibitors with both antiviral and anti-inflammatory properties. The interactions of the compounds within the SARS-CoV-2 MPro binding site were analyzed through molecular docking when data from crystallographic structures were unavailable. 18 compounds were selected and classified into five different superclasses. Five of them exhibit high potency against MPro: GC-376, baicalein, naringenin, heparin, and carmofur, with IC₅₀ values below 0.2 μM. The MPro inhibitors selected have the potential to alleviate lung edema and decrease cytokine release. These molecules mainly target three critical inflammatory pathways: NF-κB, JAK/STAT, and MAPK, all previously associated with COVID-19 pathogenesis. The structures of the compounds occupy the S1/S2 substrate binding subsite of the MPro. They interact with residues from the catalytic dyad (His41 and Cys145) and/or with the oxyanion hole (Gly143, Ser144, and Cys145), which are pivotal for substrate recognition. The MPro SARS-CoV-2 inhibitors with potential anti-inflammatory activities present here could be optimized for maximum efficacy and safety and be explored as potential treatment of both mild and severe COVID-19.

2024-07-19·ACS Chemical Biology

High-Resolution Substrate Specificity Profiling of SARS-CoV-2 M^pro; Comparison to SARS-CoV M^pro

Article

作者: Yaghi, Rasha M ; Wylie, Dennis C ; Andrews, Collin L ; Iverson, Brent L

The SARS-CoV-2 M^pro protease from COVID-19 cleaves the pp1a and pp2b polyproteins at 11 sites during viral maturation and is the target of Nirmatrelvir, one of the two components of the frontline treatment sold as Paxlovid. We used the YESS 2.0 platform, combining protease and substrate expression in the yeast endoplasmic reticulum with fluorescence-activated cell sorting and next-generation sequencing, to carry out the high-resolution substrate specificity profiling of SARS-CoV-2 M^pro as well as the related SARS-CoV M^pro from SARS 2003. Even at such a high level of resolution, the substrate specificity profiles of both enzymes are essentially identical. The population of cleaved substrates isolated in our sorts is so deep, the relative catalytic efficiencies of the different cleavage sites on the SARS-CoV-2 polyproteins pp1a and pp2b are qualitatively predicted. These results not only demonstrated the precise and reproducible nature of the YESS 2.0/NGS approach to protease substrate specificity profiling but also should be useful in the design of next generation SARS-CoV-2 M^pro inhibitors, and by analogy, SARS-CoV M^pro inhibitors as well.

100 项与 SARS-CoV-2 Mpro inhibitors(University of Bonn) 相关的药物交易

登录后查看更多信息