<i>N</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-based inhibitors, such as RA-2034, 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 reverse amide inhibitors bearing N-alkyl sulfamate warheads with improved biochemical and antiviral profiles. N-methyl sulfamate acetamide 5 emerged as a lead compound with potency against both New and Old

SUBMITTER: Ghoshal A 

PROVIDER: S-EPMC12236718 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature