Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M.
The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.
Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, USA.
Andrey Yu
AY
Kovalevsky
Yunfeng
Y
Tie
Fengling
F
Liu
Peter I
PI
Boross
Yuan-Fang
YF
Wang
Sofiya
S
Leshchenko
Arun K
AK
Ghosh
Robert W
RW
Harrison
Irene T
IT
Weber
D003460:Crystallization; D018360:Crystallography, X-Ray; D000069454:Darunavir; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D019469:Indinavir / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D013449:Sulfonamides / Q000737:chemistry*
D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D019469:Indinavir; D016333:HIV Protease; D000069454:Darunavir