title: A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
abstract: 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.
authors: Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors: Masayuki
authors: M
authors: Amano
authors: Yasuhiro
authors: Y
authors: Koh
authors: Debananda
authors: D
authors: Das
authors: Jianfeng
authors: J
authors: Li
authors: Sofiya
authors: S
authors: Leschenko
authors: Yuan-Fang
authors: YF
authors: Wang
authors: Peter I
authors: PI
authors: Boross
authors: Irene T
authors: IT
authors: Weber
authors: Arun K
authors: AK
authors: Ghosh
authors: Hiroaki
authors: H
authors: Mitsuya
mesh_terms: D000595:Amino Acid Sequence; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014520:Urethane / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C522027:(2,8-dioxabicyclo(3.3.0)oct-6-yl)-N-(4-((3,4-methylenedioxyphenyl)sulfonyl-(2-methylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl) carbamate; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D014520:Urethane; D016333:HIV Protease