IC-2b4

The HIV capsid (CA) protein is a highly promising target for anti-HIV treatment due to its critical role in viral replication. Based on the optimization of 11L guided by PF74, a series of novel HIV CA inhibitors targeting the NTD-CTD interface were identified, demonstrating potent inhibitory effects against both HIV-1 and HIV-2. Notably, compound IC-2b4 (EC₅₀ = 0.08 ± 0.02 μM) exhibits twice the potency of 11L and three times that of PF74 against HIV-1. For HIV-2, IC-2a4 (EC₅₀ = 0.01 ± 0.00 μM) demonstrates twice the efficacy of 11L and 221 times that of PF74. In mechanistic studies, IC-2b4 was shown to bind directly and stably to CA, exerting robust inhibitory effects during both the early and late stages of infection-a property also observed with IC-2b3. Molecular dynamics simulations revealed that IC-2b4 forms more extensive interactions with CA compared to PF74, thereby enhancing antiviral activity. These novel antiviral compounds collectively provide valuable insights into developing anti-HIV therapies and highlight the therapeutic potential of the CA protein as a drug target.