P33.06
Background: Increased access to therapy has reduced HIV-1 morbidity and mortality, but new drug classes would further enhance treatment options and counter resistance. Acylguanidine-based molecules are active against diverse viruses. One member of this group, BIT225, is reported to inhibit HIV-1 by blocking the viroporin function of Vpu, however its clinical utility is limited by toxicity. We investigated the anti-HIV-1 activity of a novel acylguanidine compound, SM111.
Methods: We used a GFP-reporter T cell assay to test SM111's ability to inhibit replication of NL4-3 and four recombinant strains encoding major NRTI- and/or NNRTI-resistance mutations in Pol (e.g. D67N and/or K103N, respectively). Viruses were cultured in the presence of SM111 (0-100μM), AZT (NRTI; 100nM) or EFV (NNRTI; 100nM) and infected GFP+ cells were monitored by flow cytometry. Drug activity was assessed on day 6 compared to media controls. Cytotoxicity was evaluated using ViaCount (Millipore). NL4-3 was also passaged in 100μM SM111; three independent drug-resistant strains were isolated and sequenced.
Results: SM111 inhibited NL4-3 in a dose-dependent manner between 10μM and 100μM. HIV-infected cells were reduced>98% at 100μM (44.3% [42.8-46.4] in absence vs. 0.64 % [0.56-0.76] in presence of drug). Similar activity was observed against NRTI and NNRTI resistance strains (>95% reduction in all cases). In contrast to BIT225, SM111 was not toxic at any dose tested. Notably, SM111-resistant strains encoded mutations in the transmembrane of Vpu, including a 5AA deletion, a substitution or insertion of a stop codon at highly conserved W22.
Conclusions: SM111 is a novel compound that can inhibit wild type as well as NRTI- and NNRTI-resistant HIV-1 strains, indicating that it has a different mechanism of action than current drugs. Resistance patterns suggest that SM111's target is Vpu, but additional studies are necessary to explore the mechanism of this promising prototype.
Funded by CIHR and the Michael Smith Foundation for Health Research
