RNA Therapeutics Institute; Department of Biochemistry and Molecular Pharmacology
Biochemistry, Biophysics, and Structural Biology | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry
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 K i value of 1.9 nM for PRL76V, whereas the other three inhibitors had K i 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.
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Copyright © 2018 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
DOI of Published Version
ACS Omega. 2018 Sep 30;3(9):12132-12140. doi: 10.1021/acsomega.8b01683. Epub 2018 Sep 27. Link to article on publisher's site
Wong-Sam A, Wang Y, Zhang Y, Ghosh AK, Harrison RW, Weber IT. (2018). Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease. RNA Therapeutics Institute Publications. https://doi.org/10.1021/acsomega.8b01683. Retrieved from https://escholarship.umassmed.edu/rti_pubs/40
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