<i><b>N</b></i>-Alkyl Sulfamates as a New Class of nsP2 Cysteine Protease Inhibitors with Broad-Spectrum Antialphaviral Activity.

ABSTRACT: The emergence of mosquito-borne alphaviruses that cause chronic arthritis or encephalitis underscores the urgent need for broad-spectrum antiviral therapeutics. The viral nsP2 cysteine protease, which is essential for alphavirus replication, is a promising antiviral target. Vinyl sulfone covalent inhibitors potently inhibit nsP2 protease but suffer from glutathione reactivity and species-dependent systemic clearance catalyzed by glutathione S-transferase. To address these liabilities, we explored alternative electrophilic warheads and identified acetamide inhibitors bearing N-alkyl sulfamate warheads with improved biochemical and antiviral profiles. 2-((5-(2-Ethoxyphenyl)-1H-pyrazol-3-yl)amino)-2-oxoethyl methylsulfamate emerged as a lead compound with potency against

SUBMITTER: Ghoshal A 

PROVIDER: S-EPMC12621199 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature