HIV-1 Gag maturation (CA-SP1 cleavage)

Class

Maturation inhibitor (small molecule)

Notes

Source: https://pmc.ncbi.nlm.nih.gov/articles/PMC11512352/ ; https://pubmed.ncbi.nlm.nih.gov/39459843/ (VH3739937; researched 2026-08-08)

HIV-1 replication requires a final step called maturation, during which the viral protease enzyme cleaves the Gag polyprotein into its structural components: matrix, capsid, spacer peptides, nucleocapsid, and p6. One of these cleavage events, between the capsid protein and the first spacer peptide (SP1), controls the timing of capsid protein release and its assembly into the cone-shaped shell that encloses the viral genome. Maturation inhibitors act on this specific junction, binding to the site where cleavage would occur and preventing the protease from processing it. The Gag polyprotein remains incompletely processed, so the resulting virus particles cannot assemble a normal capsid and are rendered non-infectious. This mechanism differs from that of conventional protease inhibitors, which block the enzyme's active site broadly rather than a single substrate junction. Because the target is a specific viral protein sequence, efficacy depends on the exact amino acids at the CA-SP1 boundary, which vary naturally among viral strains. This mechanism matters broadly in HIV infection, and particularly for individuals whose virus has become resistant to existing antiretroviral classes, since a compound acting at a novel step in the viral life cycle can retain activity against strains resistant to protease, reverse transcriptase, or integrase inhibitors.