Abstract
Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds 4 and 5, were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PRL76V). Compound 5 exhibited the best Ki value of 1.9 nM for PRL76V, whereas the other three inhibitors had Ki values of 4.5–7.6 nM, 2–3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PRL76V compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with Lys45 and Ile47 in the flap, and with Asp30 and Thr74 in the protein core, consistent with decreased stability. Inhibitors forming additional polar interactions with the flaps or dimer interface of PRL76V were unable to compensate for the decrease in internal hydrophobic contacts. These structures provide insights for inhibitor design.
Highlights
The protease (PR) encoded by the human immunodeficiency virus (HIV) is an important drug target for treatment of the pandemic disease HIV/AIDS
Drug-resistant mutation L76V is rare in clinical isolates of HIV; this mutation alone acts to decrease the stability of the PR dimer, alters precursor processing, and reduces viral fitness.[20,24,37]
We examined the effect of four antiviral inhibitors, two clinical drugs and two investigational inhibitors, on the single mutant PRL76V
Summary
The protease (PR) encoded by the human immunodeficiency virus (HIV) is an important drug target for treatment of the pandemic disease HIV/AIDS. 3 forms direct hydrogen bonds with the main chain atoms of flap residues, Gly[48], Ile[50], and Ile50′ in both wildtype and mutant PRs. Inhibitor 3 shows two alternative conformations in both complexes with 70:30 relative occupancy; the minor conformation with 30% occupancy loses a hydrogen bond to the amide of Asp[29] in the mutant structure. In the major conformation of Asp30′ in the mutant, the carboxylate side chain is positioned to form a shorter hydrogen bond interaction with the aniline amino group relative to the wild-type complex, whereas the hydrogen bond of the main chain amide of Asp30′. Increased conformational flexibility of the flaps in the PRL76V mutant compared to the wild-type enzyme was reported in 1 ns molecular dynamics simulations of the complexes with inhibitor 2 consistent with increased calculated interaction free energy and clinical resistance.[36]
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