Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease

- Inhibitors against MDR HIV-1 protease were designed, synthesized and evaluated.
- Lead peptide (6a) showed potent inhibition (IC50: 4.4 nM) of MDR HIV-1 protease.
- (6a) Showed favorable binding isotherms against NL4-3 and MDR proteases.
- (6a) Induced perturbations in the 15N-HSQC spectrum of MDR HIV-1 protease.
- Molecular modeling suggested that (6a) may induce total flap closure inMDR protease.