Synthesis, screening and validation of cysteine-reactive fragments as chikungunya virus protease inhibitors

IF 2.5 4区 医学 Q3 CHEMISTRY, MEDICINAL
Junming He , Henry Illingworth , Sven Ullrich , Pritha Ghosh , Jennifer Ton , Colin J. Jackson , Christoph Nitsche
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Abstract

Alphaviruses like the Chikungunya virus cause severe outbreaks; however, no specific treatments are available. Their viral replication depends on the nsP2 cysteine protease, a promising but underexplored target for drug discovery. In this study, we report a covalent fragment screening against Chikungunya virus nsP2 protease, resulting in the identification of three inhibitors that can serve as starting points for future drug development. Careful validation proved indispensable in eliminating false-positive hits from a Förster resonance energy transfer (FRET)-based inhibition assay, wherein interference was caused by the inner filter effect between the fluorescent substrate and coloured compounds. Jump-dilution experiments accompanied by reactivity studies with cysteine and the recombinant protein indicate covalent inhibition via thia-Michael addition. We further demonstrate cross-inhibition of the related alphavirus nsP2 protease from Sindbis virus. The study provides early insights into nsP2 inhibition by electrophilic fragments featuring non-promiscuous N-arylacrylamides, thus advancing the search for antivirals targeting Chikungunya and other alphaviruses of concern.

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来源期刊
CiteScore
5.70
自引率
3.70%
发文量
463
审稿时长
27 days
期刊介绍: Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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