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

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

Larisa Ivanova  1 , Kai Rausalu  2 , Eva Žusinaite  2 , Jaana Tammiku-Taul  1 , Andres Merits  2 , Mati Karelson  1
Affiliations

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

Larisa Ivanova et al. ACS Omega. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Calculated binding modes of compounds 1 (a), 10 (b), 10b (c), 10c (d), and nitazoxanide (e) in the active site of CHIKV nsP2 (PDB ID: 3TRK).
Figure 2
Figure 2
2D summary diagram of the MD-calculated contacts between CHIKV nsP2 (PDB ID: 3TRK) and compounds 1 (a), 10 (b), 10b (c), and 10c (d). Interactions that occur more than 10% of the simulation time are shown.
Figure 3
Figure 3
(a) Effects of compounds 1, 10, 10b, and 10c (indicated on the top) used at a concentration of 1 mM on the ability of CHIKV nsP2 to cleave a recombinant protein substrate. Names of the proteins are indicated on the right, and molecular masses of marker bands are indicated on the left. (b) Western blot analysis. BHK-21 cells infected with CHIKV-NanoLuc (MOI 10) were treated with increasing concentrations of compound 10. Cell lysates were collected 6 h post infection and run on 10% SDS-PAGE, and proteins were transferred onto the PVDF membrane. CHIKV proteins were detected using the respective rabbit primary antibodies and secondary anti-rabbit IRDye680-conjugated fluorescent antibodies. Loading control—β-actin—was detected using the primary mouse and secondary anti-mouse IRDye800-conjugated antibody. Names of the proteins are indicated on the left, and molecular masses of marker bands are indicated on the right. Neg: BHK-21 cells treated with 1% DMSO; Pos: infected BHK-21 cells treated with 1% DMSO (no inhibitor).
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