title: The higher barrier of darunavir and tipranavir resistance for HIV-1 protease.
abstract: Darunavir and tipranavir are two inhibitors that are active against multi-drug resistant (MDR) HIV-1 protease variants. In this study, the invitro inhibitory efficacy was tested against a MDR HIV-1 protease variant, MDR 769 82T, containing the drug resistance mutations of 46L/54V/82T/84V/90M. Crystallographic and enzymatic studies were performed to examine the mechanism of resistance and the relative maintenance of potency. The key findings are as follows: (i) The MDR protease exhibits decreased susceptibility to all nine HIV-1 protease inhibitors approved by the US Food and Drug Administration (FDA), among which darunavir and tipranavir are the most potent; (ii) the threonine 82 mutation on the protease greatly enhances drug resistance by altering the hydrophobicity of the binding pocket; (iii) darunavir or tipranavir binding facilitates closure of the wide-open flaps of the MDR protease; and (iv) the remaining potency of tipranavir may be preserved by stabilizing the flaps in the inhibitor-protease complex while darunavir maintains its potency by preserving protein main chain hydrogen bonds with the flexible P2 group. These results could provide new insights into drug design strategies to overcome multi-drug resistance of HIV-1 protease variants.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Brunzelle
authors.forename: Iulia A
authors.initials: IA
authors.lastname: Kovari
authors.forename: Tamaria G
authors.initials: TG
authors.lastname: Dewdney
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Reiter
authors.forename: Ladislau C
authors.initials: LC
authors.lastname: Kovari
mesh_terms: D000595:Amino Acid Sequence; D000069454:Darunavir; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D009154:Mutation; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir; C107201:tipranavir