Buckyballs to fight pandemic: Water-soluble fullerene derivatives with pendant carboxylic groups emerge as a new family of promising SARS-CoV-2 inhibitors

Olga A Kraevaya; Valeriya S Bolshakova; Alexander V Slita; Iana L Esaulkova; Alexander V Zhilenkov; Mikhail G Mikhalsky; Ekaterina O Sinegubova; Ilya I Voronov; Alexander S Peregudov; Alexander F Shestakov; Vladimir V Zarubaev; Pavel A Troshin

doi:10.1016/j.bioorg.2024.108097

Buckyballs to fight pandemic: Water-soluble fullerene derivatives with pendant carboxylic groups emerge as a new family of promising SARS-CoV-2 inhibitors

Bioorg Chem. 2024 Dec 24:154:108097. doi: 10.1016/j.bioorg.2024.108097. Online ahead of print.

Affiliations

¹ Federal Research Center for Problems of Chemical Physics and Medicinal Chemistry of RAS, Semenov Prospect 1, Chernogolovka 142432, Russia. Electronic address: [email protected].
² Federal Research Center for Problems of Chemical Physics and Medicinal Chemistry of RAS, Semenov Prospect 1, Chernogolovka 142432, Russia.
³ St. Petersburg Pasteur Institute, Mira st. 14, St. Petersburg 197101, Russia.
⁴ A.N. Nesmeyanov Institute of Organoelement Compounds of RAS, Vavylova St. 28, B- 334, Moscow 119991, Russia.
⁵ Federal Research Center for Problems of Chemical Physics and Medicinal Chemistry of RAS, Semenov Prospect 1, Chernogolovka 142432, Russia; Department of Fundamental Physics & Chemical Engineering, M.V. Lomonosov Moscow State University, Leninskie Gory 1/51, Moscow 119991, Russia.
⁶ St. Petersburg Pasteur Institute, Mira st. 14, St. Petersburg 197101, Russia. Electronic address: [email protected].
⁷ Federal Research Center for Problems of Chemical Physics and Medicinal Chemistry of RAS, Semenov Prospect 1, Chernogolovka 142432, Russia; Zhengzhou Research Institute of HIT, Longyuan East 7th 26, Jinshui District, Zhengzhou, Henan Province 450003, China. Electronic address: [email protected].

PMID: 39729769
DOI: 10.1016/j.bioorg.2024.108097

Abstract

Herein, we present the first experimental study of individual water-soluble fullerene derivatives proving their ability to inhibit SARS-CoV-2 in vitro. The initial screening allowed us to identify a few new compounds that have demonstrated pronounced antiviral activity with IC₅₀ values as low as 390 nM and selectivity indexes reaching 214. Time-of-addition analysis and molecular docking results suggested that the viral protease and/or the spike protein are the most probable targets inhibited by the fullerene derivatives. Further rational design of fullerene derivatives might lead to the development of compounds with further enhanced antiviral activity and decreased toxicity.

Keywords: Antiviral activity; Fullerene derivatives; Mechanism; SARS-CoV-2.