Abstract
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 (EC(50) = 0.59 nM; SI > 34,525) and maintained efficacy against a panel of drug-resistant strains (EC(50) range from 0.34 to 9.12 nM) and clinical isolated strains (EC(50) range from 0.11 to 1.78 nM). Mechanism of action studies confirmed its ability to inhibit the integrase enzyme (IC(50) = 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.