TY - JOUR
T1 - Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M
AU - Kovalevsky, Andrey Yu
AU - Tie, Yunfeng
AU - Liu, Fengling
AU - Boross, Peter I.
AU - Wang, Yuan Fang
AU - Leshchenko, Sofiya
AU - Ghosh, Arun K.
AU - Harrison, Robert W.
AU - Weber, Irene T.
PY - 2006/2/23
Y1 - 2006/2/23
N2 - 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 (Ki) of TMC-114 for mutants PRD30N, PRI50V, and PRL90M 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 Å) crystal structures of PR mutant complexes with TMC-114. In PRD30N, 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 PRI50V the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PRL90M 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.
AB - 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 (Ki) of TMC-114 for mutants PRD30N, PRI50V, and PRL90M 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 Å) crystal structures of PR mutant complexes with TMC-114. In PRD30N, 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 PRI50V the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PRL90M 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.
UR - http://www.scopus.com/inward/record.url?scp=33144466093&partnerID=8YFLogxK
U2 - 10.1021/jm050943c
DO - 10.1021/jm050943c
M3 - Article
C2 - 16480273
AN - SCOPUS:33144466093
SN - 0022-2623
VL - 49
SP - 1379
EP - 1387
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -
