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Antimicrob. Agents Chemother. doi:10.1128/AAC.01413-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A NOVEL bis-TETRAHYDROFURANYLURETHANE-CONTAINING NONPEPTIDIC PROTEASE INHIBITOR (PI) GRL-98065 POTENT AGAINST MULTI-PI-RESISTANT HIV IN VITRO

Department of Infectious Diseases and Department of Hematology, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907; Department of Biology, Georgia State University, Atlanta, GA 30303; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

^* To whom correspondence should be addressed. Email: hm21q{at}nih.gov.

	Abstract

We designed, synthesized, and identified GRL-98065, a novel non-peptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived non-peptide 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 (EC₅₀: 0.0002-0.0005 µM) with minimal cytotoxicity (CC₅₀: 35.7 µM in CD4⁺ MT-2 cells). GRL-98065 blocked the infectivity and replication of each of HIV-1_NL4-3 variants exposed to and selected by up to 5 µM concentration of saquinavir, indinavir, nelfinavir, or ritonavir, and 1 µM concentration of lopinavir, or atazanavir (EC₅₀: 0.0015 - 0.0075 µM), although it was less active against HIV-1_NL4-3 selected by amprenavir (EC₅₀: 0.032 µM). GRL-98065 was also potent against multi-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, as well as 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 multi-PI-resistant HIV-1 variants. The present data demonstrate that the privileged non-peptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.

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