Biological chemistry 2017 05 19() doi 10.1515/hsz-2017-0107
The efficacy of HIV-1 protease inhibition therapies is often compromised by the emergence of mutations in the protease molecule that reduces the binding affinity of inhibitors while maintaining viable catalytic activity and affinity for natural substrates. In the present study, we used a recombinant HIV-1 C-SA protease and a recently reported variant for inhibition (Ki, IC50) and thermodynamic studies against nine clinically used inhibitors. This is the first time that binding free energies for C-SA PR and the mutant are reported. This variant protease harbours a mutation and insertion (I36↑TT) at position 36 of the C-SA HIV-1 protease, and did not show a significant difference on the catalytic effect of the HIV-1 protease. However, the nine clinically-approved HIV PR drugs used in this study demonstrated weaker inhibition and lower binding affinities toward the variant when compared to the wild-type HIV-1 protease. All the protease inhibitors, except Amprenavir and Ritonavir exhibited a significant decrease in binding affinity (p<0.0001). Darunavir and Nelfinavir exhibited the weakest binding affinity, 155- and 95- fold decreases respectively, toward the variant. Vitality values for the variant protease, against the seven selected protease inhibitors, confirm the impact of the mutation and insertion on the South African HIV-1 subtype C protease. This information has important clinical application for thousands of patients in Sub-Saharan Africa.