Quinazolinone-based subchemotypes for targeting HIV-1 capsid protein: design and synthesis

The recent FDA-approval of lenacapavir (LEN, GS-6207) and the subsequent discovery of GSK878 strongly validate HIV-1 capsid protein (CA) as a target for antiviral development. However, multiple single mutations drastically reduced the susceptibility of HIV-1 to both GS-6207 and GSK878, necessitating the design and synthesis of novel sub-chemotypes. With the aid of induced-fit molecular docking, we have designed a few new hybrids combining the quinazolinone scaffold of GSK878 and an N-terminal cap from other CA-targeting chemotypes. We have also worked out a modular synthesis of these novel subtypes. Although these new analogs only weakly inhibited HIV-1 and produced relatively small shifts in the thermal shift assay against pre-assembled CA hexamers, the design and synthesis reported herein inform future design and synthesis of structurally more elaborate analogs for improved potency.