Medrano Francisco J, de la Hoz-Rodríguez Sergio, Martí Sergio, Arafet Kemel, Schirmeister Tanja, Hammerschmidt Stefan J, Müller Christin, González-Martínez Águeda, Santillana Elena, Ziebuhr John, Romero Antonio, Zimmer Collin, Weldert Annabelle, Zimmermann Robert, Lodola Alessio, Świderek Katarzyna, Moliner Vicent, González Florenci V
Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12071, Castelló, Spain.
Commun Chem. 2024 Jan 18;7(1):15. doi: 10.1038/s42004-024-01104-7.
The coronavirus disease 2019 (COVID-19) pandemic continues to represent a global public health issue. The viral main protease (M) represents one of the most attractive targets for the development of antiviral drugs. Herein we report peptidyl nitroalkenes exhibiting enzyme inhibitory activity against M (K: 1-10 μM) good anti-SARS-CoV-2 infection activity in the low micromolar range (EC: 1-12 μM) without significant toxicity. Additional kinetic studies of compounds FGA145, FGA146 and FGA147 show that all three compounds inhibit cathepsin L, denoting a possible multitarget effect of these compounds in the antiviral activity. Structural analysis shows the binding mode of FGA146 and FGA147 to the active site of the protein. Furthermore, our results illustrate that peptidyl nitroalkenes are effective covalent reversible inhibitors of the M and cathepsin L, and that inhibitors FGA145, FGA146 and FGA147 prevent infection against SARS-CoV-2.
2019年冠状病毒病（COVID-19）大流行仍然是一个全球公共卫生问题。病毒主要蛋白酶（M）是开发抗病毒药物最具吸引力的靶点之一。在此，我们报道了肽基硝基烯烃对M具有酶抑制活性（K：1-10 μM），在低微摩尔范围内具有良好的抗SARS-CoV-2感染活性（EC：1-12 μM），且无明显毒性。对化合物FGA145、FGA146和FGA147的进一步动力学研究表明，这三种化合物均抑制组织蛋白酶L，表明这些化合物在抗病毒活性中可能具有多靶点作用。结构分析显示了FGA146和FGA147与该蛋白活性位点的结合模式。此外，我们的结果表明，肽基硝基烯烃是M和组织蛋白酶L的有效共价可逆抑制剂，并且抑制剂FGA145、FGA146和FGA147可预防SARS-CoV-2感染。
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