1,3-Thiazolbenzamide Derivatives as Chikungunya Virus nsP2 Protease Inhibitors

Larisa Ivanova; Kai Rausalu; Eva Žusinaite; Jaana Tammiku-Taul; Andres Merits; Mati Karelson

doi:10.1021/acsomega.0c06191

1,3-Thiazolbenzamide Derivatives as Chikungunya Virus nsP2 Protease Inhibitors

ACS Omega. 2021 Feb 17;6(8):5786-5794. doi: 10.1021/acsomega.0c06191. eCollection 2021 Mar 2.

Authors

Larisa Ivanova¹, Kai Rausalu², Eva Žusinaite², Jaana Tammiku-Taul¹, Andres Merits², Mati Karelson¹

Affiliations

¹ Institute of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia.
² Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.

Abstract

Chikungunya fever results from an infection with Chikungunya virus (CHIKV, genus Alphavirus) that is prevalent in tropical regions and is spreading fast to temperate climates with documented outbreaks in Europe and the Americas. Currently, there are no available vaccines or antiviral drugs for prevention or treatment of Chikungunya fever. The nonstructural proteins (nsPs) of CHIKV responsible for virus replication are promising targets for the development of new antivirals. This study was attempted to find out new potential inhibitors of CHIKV nsP2 protease using the ligand-based drug design. Two compounds 10 and 10c, identified by molecular docking, showed antiviral activity against CHIKV with IC₅₀ of 13.1 and 8.3 μM, respectively. Both compounds demonstrated the ability to inhibit the activity of nsP2 in a cell-free assay, and the impact of compound 10 on virus replication was confirmed by western blot. The molecular dynamics study of the interactions of compounds 10 and 10c with CHIKV nsP2 showed that a possible mechanism of action of these compounds is the blocking of the active site and the catalytic dyad of nsP2.