Lipid-Optimized Sulfone-Bridged Cidofovir Prodrugs as Potent Antivirals Against Orthopoxviruses

The unprecedented global mpox outbreak highlights the
urgent need
for novel orthopoxvirus antivirals. In this study, we rationally designed
and synthesized a series of cidofovir (CDV) prodrugs conjugated with
diverse lipid chains via sulfur-containing bridge moieties. Structure–activity
relationship analyses identified the sulfone group as optimal, with
a C2H4 linker and an approximately 20-atom chain
length providing ideal antiviral potency. Compound 13f exhibited antiviral activity against vaccinia virus (VACV) comparable
to that of the reference brincidofovir (BCV), while 13i displayed 8.2-fold enhanced potency. Both derivatives demonstrated
superior potency against monkeypox virus (MPXV) compared to BCV. Stability
tests in biorelevant media and pharmacokinetic evaluations confirmed
favorable oral formulation characteristics for 13f and 13i. Notably, 13i exhibited a favorable safety
profile and significant therapeutic efficacy in both VACV-challenged
BALB/c and MPXV-challenged severe combined immunodeficiency mouse
models. Through systematic lipid-chain optimization, we identified 13i as a promising antiviral candidate with enhanced efficacy
and favorable pharmaceutical properties.