The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity

• DOI: 10.1016/j.str.2024.10.025
• Publication Date: 2024-11-13T16:32:09Z
• Authors: María Ángeles Már...; Clara M. Santiveri; Patricia de León; Sergio Camero; Ramón Campos-Olivas; M. Ángeles Jiménez; Margarita Sáiz; Beatriz González; José Manuel Pérez...
• Keywords: Riluzole; C-terminus

Peer reviewed<br/>Funding was provided by MCIN/AEI/10.13039/501100011033/grants: PID2020-112821GB-I00 and PID2023-146361NB-I00 (also funded by “ERDF A way of making Europe”) to J.M.P.-C. and M.A.J; and by PID2020-117400GB-100 to B.G. 19F-NMR library and experiments was accessed by payment to the service at Spectroscopy and Nuclear Magnetic Resonance Unit of the Spanish National Cancer Research Center.<br/>Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site. Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals.<br/>18 pages, 6 figures, 1 table<br/>