作者: Sekirnik, Andreja ; Tsuge, Hideaki ; Lieske, Julia ; Usenik, Aleksandra ; Ewert, Wiebke ; Meents, Alke ; Hinrichs, Winfried ; Dretnik, Klemen ; Lindič, Nataša ; Loboda, Jure ; Turk, Dušan ; Reinke, Patrick Y A ; Turk, Vito ; Karničar, Katarina ; Chapman, Henry N ; Falke, Sven ; Herrmann, Alexander ; Günther, Sebastian ; Ebert, Gregor

Emerging RNA viruses, including SARS-CoV-2, continue to be a major threat. Cell entry of SARS-CoV-2 particles via the endosomal pathway involves cysteine cathepsins. Due to ubiquitous expression, cathepsin L (CatL) is considered a promising drug target in the context of different viral and lysosome-related diseases. We characterized the anti-SARS-CoV-2 activity of a set of carbonyl- and succinyl epoxide-based inhibitors, which were previously identified as inhibitors of cathepsins or related cysteine proteases. Calpain inhibitor XII, MG-101, and CatL inhibitor IV possess antiviral activity in the very low nanomolar EC₅₀ range in Vero E6 cells and inhibit CatL in the picomolar K_i range. We show a relevant off-target effect of CatL inhibition by the coronavirus main protease α-ketoamide inhibitor 13b. Crystal structures of CatL in complex with 14 compounds at resolutions better than 2 Å present a solid basis for structure-guided understanding and optimization of CatL inhibitors toward protease drug development.

2024-03-01·Journal of Medical Virology

Improved fluorescence‐based assay for rapid screening and evaluation of SARS‐CoV‐2 main protease inhibitors

Article

作者: Zhou, Jiahao ; Yan, Haohao ; Liu, Xiaoping ; Shang, Chao ; Yan, Gangan ; Chen, Yunyu ; Zhang, Rui

AbstractThe outbreak of coronavirus disease 2019 (COVID‐19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a global threat to human health. In parallel with vaccines, efficacious antivirals are urgently needed. SARS‐CoV‐2 main protease (Mpro) is an attractive drug target for antiviral development owing to its key roles in virus replication and host immune evasion. Due to the limitations of currently available methods, the development of novel high‐throughput screening assays is of the highest importance for the discovery of Mpro inhibitors. In this study, we first developed an improved fluorescence‐based assay for rapid screening of Mpro inhibitors from an anti‐infection compound library using a versatile dimerization‐dependent red fluorescent protein (ddRFP) biosensor. Utilizing this assay, we identified MG‐101 as a competitive Mpro inhibitor in vitro. Moreover, our results revealed that ensitrelvir is a potent Mpro inhibitor, but baicalein, chloroquine, ebselen, echinatin, and silibinin are not. Therefore, this robust ddRFP assay provides a faithful avenue for rapid screening and evaluation of Mpro inhibitors to fight against COVID‐19.

2022-01-01·Computational and Structural Biotechnology Journal

Potential drug discovery for COVID-19 treatment targeting Cathepsin L using a deep learning-based strategy

Article

作者: Yang, Jin-Kui ; Yang, Wei-Li ; Tang, Yan-Hong ; Zhao, Jin-Cun ; Li, Yu-Yang ; Cao, Xi ; Zhao, Miao-Miao ; Huat Tan, Sia ; Sun, Jing ; Li, Qi

Cathepsin L (CTSL), a cysteine protease that can cleave and activate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, could be a promising therapeutic target for coronavirus disease 2019 (COVID-19). However, there is still no clinically available CTSL inhibitor that can be used. Here, we applied Chemprop, a newly trained directed-message passing deep neural network approach, to identify small molecules and FDA-approved drugs that can block CTSL activity to expand the discovery of CTSL inhibitors for drug development and repurposing for COVID-19. We found 5 molecules (Mg-132, Z-FA-FMK, leupeptin hemisulfate, Mg-101 and calpeptin) that were able to significantly inhibit the activity of CTSL in the nanomolar range and inhibit the infection of both pseudotype and live SARS-CoV-2. Notably, we discovered that daptomycin, an FDA-approved antibiotic, has a prominent CTSL inhibitory effect and can inhibit SARS-CoV-2 pseudovirus infection. Further, molecular docking calculation showed stable and robust binding of these compounds with CTSL. In conclusion, this study suggested for the first time that Chemprop is ideally suited to predict additional inhibitors of enzymes and revealed the noteworthy strategy for screening novel molecules and drugs for the treatment of COVID-19 and other diseases with unmet needs.

100 项与 MG-101 相关的药物交易

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