GRL-142 is a potent HIV-1 protease inhibitor capable of crossing the blood-brain barrier. It exhibits exceptional inhibitory activity against both wild-type and multi-drug resistant strains (IC50=0.0094 nM). GRL-142 employs a unique scaffold-binding mechanism, synergistically engaging with the P2/P2' segments through fluorine-mediated stable interactions to maintain its bioactive conformation. It adapts to p51HIV-1 protease mutants by directly interacting with flap-tip residues to maintain flap-closed states. Furthermore, GRL-142 disrupts the flap-water hydrogen bond network in wild-type protease, effectively blocking viral replication. This compound is applicable to studies of HIV-1 infection and associated neurocognitive disorders (HAND).