作者: Sekirnik, Andreja ; Tsuge, Hideaki ; Lieske, Julia ; Ewert, Wiebke ; Usenik, Aleksandra ; 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 ; Ebert, Gregor ; Günther, Sebastian

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.

2022-05-06·Cardiovascular Research1区 · 医学

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size

1区 · 医学

Article

作者: Smith, Godfrey L ; Oldroyd, Keith G ; Shaukat, Aadil ; Corcoran, David ; Petrie, Mark C ; Berry, Colin ; Carrick, David ; Lee, Mathew M Y ; Hawksby, Catherine ; Nicklin, Stuart A ; McClure, John ; He, Weihong ; Martin, Tamara ; Eteiba, Hany ; Watkins, Stuart ; Channon, Keith M ; McArthur, Lisa ; Nather, Katrin ; Ford, Kristopher ; McEntegart, Margaret ; Loughrey, Christopher M ; Riddell, Alexandra ; McCarroll, Charlotte S ; Lindsay, Mitchell M ; Rocchiccioli, Paul ; Good, Richard ; Mangion, Kenneth ; Zaeri, Ali ; O’Toole, Dylan ; Elliott, Elspeth B ; Hood, Stuart ; Davie, Andrew

AbstractAimsIdentifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury.Methods and resultsWe found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis.ConclusionOur findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.

2022-03-24·Journal of Medicinal Chemistry1区 · 医学

Efficient Identification of Anti-SARS-CoV-2 Compounds Using Chemical Structure- and Biological Activity-Based Modeling

1区 · 医学

Article

作者: Zhu, Wei ; Huang, Ruili ; Xu, Tuan ; Chen, Catherine Z. ; Xu, Miao ; Zheng, Wei ; Zhang, Qi

Identification of anti-SARS-CoV-2 compounds through traditional high-throughput screening (HTS) assays is limited by high costs and low hit rates. To address these challenges, we developed machine learning models to identify compounds acting via inhibition of the entry of SARS-CoV-2 into human host cells or the SARS-CoV-2 3-chymotrypsin-like (3CL) protease. The optimal classification models achieved good performance with area under the receiver operating characteristic curve (AUC-ROC) values of >0.78. Experimental validation showed that the best performing models increased the assay hit rate by 2.1-fold for viral entry inhibitors and 10.4-fold for 3CL protease inhibitors compared to those of the original drug repurposing screens. Twenty-two compounds showed potent (<5 μM) antiviral activities in a SARS-CoV-2 live virus assay. In conclusion, machine learning models can be developed and used as a complementary approach to HTS to expand compound screening capacities and improve the speed and efficiency of anti-SARS-CoV-2 drug discovery.

100 项与 CAA-0225 相关的药物交易

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