Anti-HIV-1 Activity of the Integrase Strand Transfer Inhibitor ACC017

HIV-1 integrase strand transfer inhibitors (INSTIs) are pivotal to antiretroviral therapy. However, the emergence of drug-resistant mutations necessitates the development of new agents. Here, we present ACC017 as a novel INSTI candidate. ACC017 demonstrated potent activity against the laboratory-adapted HIV-1_IIIB strain (EC₅₀ = 0.59 nM; SI > 34,525) and maintained efficacy against a panel of drug-resistant strains (EC₅₀ range from 0.34 to 9.12 nM) and clinical isolated strains (EC₅₀ range from 0.11 to 1.78 nM). Mechanism of action studies confirmed its ability to inhibit the integrase enzyme (IC₅₀ = 9.19 nM) and effectively block viral genome integration. Notably, in vitro resistance selection primarily yielded D232N and R263K mutations, without the emergence of G140S/A/C/R or Q148H/R/K. This promising profile, combined with synergistic interactions with other antiretroviral drugs, positions ACC017 as a potential therapeutic option.