Highly drug-resistant HIV-1 protease reveals decreased intra-subunit interactions due to clusters of mutations.

ABSTRACT: Drug-resistance is a serious problem for treatment of the HIV/AIDS pandemic. Potent clinical inhibitors of HIV-1 protease show several orders of magnitude worse inhibition of highly drug-resistant variants. Hence, the structure and enzyme activities were analyzed for HIV protease mutant HIV-1 protease (EC 3.4.23.16) (PR) with 22 mutations (PRS5B) from a clinical isolate that was selected by machine learning to represent high-level drug-resistance. PRS5B has 22 mutations including only one (I84V) in the inhibitor binding site; however, clinical inhibitors had poor inhibition of PRS5B activity with kinetic inhibition value (K_i ) values of 4-1000 nm or 18- to 8000-fold worse than for wild-type PR. High-resolution crystal structures of PRS5B complexes with the best inhibitors, ampre

SUBMITTER: Kneller DW 

PROVIDER: S-EPMC7343616 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature