The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection.

L Delang,C Li,D Jochmans,E J Snijder,M J Van Hemert,I C Albulescu,T De Burghgraeve,N A Segura Guerrero,B Coutard,A Gigante,J Neyts,E Decroly,G Quérat,G Piorkowski,M J Pérez-Pérez,B Canard,A Tas,P Leyssen

doi:10.1038/srep31819

Abstract

The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.

Highlights

MADTP-393 18 ± 6.4a 8.2 ± 2.2b 1.4 ± 0.3b 35 ± 10b (T-705, approved in Japan for the treatment of influenza infections) exerts anti-Chikungunya virus (CHIKV) activity in vitro and in a mouse model[12]
We here report on the unique molecular mechanism by which these compounds inhibit CHIKV replication, through targeting the alphavirus capping machinery
Based on the initial hit MADTP-314 (Fig. 1), several series of MADTP compounds were synthesized and their efficacy was tested against the laboratory-adapted CHIKV strain 89914

Summary

Introduction

MADTP-393 18 ± 6.4a 8.2 ± 2.2b 1.4 ± 0.3b 35 ± 10b (T-705, approved in Japan for the treatment of influenza infections) exerts anti-CHIKV activity in vitro and in a mouse model[12]. Several other molecules with in vitro anti-CHIKV activity have been reported[13], but to our knowledge, none of these molecules have progressed towards further development. We recently identified - in a large scale cell-based antiviral screening campaign - 3-(3′-acetylphenyl)-5-met hyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one (MADTP-314) as a selective inhibitor of CHIKV replication. Following initial hit-optimization more potent analogs were obtained[14]. We here report on the unique molecular mechanism by which these compounds inhibit CHIKV replication, through targeting the alphavirus capping machinery

Methods

Results

Conclusion