Novel Analogues of the Chikungunya Virus Protease Inhibitor: Molecular Design, Synthesis, and Biological Evaluation

Larisa Ivanova; Kai Rausalu; Maksim Ošeka; Dzmitry G Kananovich; Eva Žusinaite; Jaana Tammiku-Taul; Margus Lopp; Andres Merits; Mati Karelson

doi:10.1021/acsomega.1c00625

Novel Analogues of the Chikungunya Virus Protease Inhibitor: Molecular Design, Synthesis, and Biological Evaluation

ACS Omega. 2021 Apr 14;6(16):10884-10896. doi: 10.1021/acsomega.1c00625. eCollection 2021 Apr 27.

Authors

Larisa Ivanova¹, Kai Rausalu², Maksim Ošeka³, Dzmitry G Kananovich³, Eva Žusinaite², Jaana Tammiku-Taul¹, Margus Lopp³, 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.
³ Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia Tee 15, 12618 Tallinn, Estonia.

Abstract

The Chikungunya virus (CHIKV) is an arbovirus belonging to the genus Alphavirus of the Togaviridae family. CHIKV is transmitted by the mosquitoes and causes Chikungunya fever. CHIKV outbreaks have occurred in Africa, Asia, Europe, and the countries of Indian and Pacific Oceans. In 2013, CHIKV cases were registered for the first time in the Americas on the Caribbean islands. There is currently no vaccine to prevent or medicines to treat CHIKV infection. The CHIKV nonstructural protease (nsP2) is a promising potential target for the development of drugs against CHIKV infection because this protein is one of the key components of the viral replication complex and is involved in multiple steps of virus infection. In this work, novel analogues of the potential CHIKV nsP2 protease inhibitor, first reported by Das et al. in 2016, were identified using molecular modeling methods, synthesized, and evaluated in vitro. The optimization of the structure of the inhibitor allowed to increase the antiviral activity of the compound 2-10 times. The possible mechanism of action of the identified potential inhibitors of the CHIKV nsP2 protease was studied in detail using molecular dynamics (MD) simulations. According to the MD results, the most probable mechanism of action is the blocking of conformational changes in the nsP2 protease required for substrate recognition and binding.