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001-es BibID:	BIBFORM003546
Első szerző:	Amano, Masayuki
Cím:	A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro / Amano M., Koh Y., Das D., Li J., Leschenko S., Wang Y.F., Boross P.I., Weber I.T., Ghosh A.K., Mitsuya H.
Dátum:	2007
Megjegyzések:	We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Antimicrobial agents and chemotherapy. - 51 : 6 (2007), p. 2143-2155. -
További szerzők:	Koh, Yasuhiro Das, Debananda Li, Jianfeng Leschenko, Sofiya Wang, Yuan-Fang Boross Péter (1972-) (biokémikus, vegyész) Weber, Irene T. Ghosh, Arun K. Mitsuya, Hiroaki
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001-es BibID:	BIBFORM019931
Első szerző:	Kovalevsky, Andrey Yu
Cím:	Susceptibility of Potent Antiviral Inhibitor to Highly Drug Resistant Mutations D30N, I50V and L90M of HIV-1 Protease / Kovalevsky Andrey Yu., Tie Yunfeng, Liu Fengling, Boross Peter I., Wang Yuan-Fang, Leshchenko Sofiya, Ghosh Arun K., Harrison Robert W., Weber Irene T.
Dátum:	2006
ISSN:	0022-2623
Megjegyzések:	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.
Tárgyszavak:	Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Journal Of Medicinal Chemistry. - 49 : 4 (2006), p. 1379-1387. -
További szerzők:	Tie, Yunfeng Liu, Fengling Boross Péter (1972-) (biokémikus, vegyész) Wang, Yuan-Fang Leschenko, Sofiya Ghosh, Arun K. Harrison, Robert W. Weber, Irene T.
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