AAC Accepts, published online ahead of print on 27 October 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00689-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

GRL-02031: A Novel Nonpeptidic Protease Inhibitor (PI) Containing A Stereochemically Defined Fused Cyclopentanyltetrahydrofuran (Cp-THF) Potent Against Multi-PI-Resistant HIV-1 In Vitro

Yasuhiro Koh, Debananda Das, Sofiya Leschenko, Hirotomo Nakata, Hiromi Ogata-Aoki, Masayuki Amano, Maki Nakayama, Arun K. Ghosh, and Hiroaki Mitsuya^*

Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; and Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IL 47907, USA

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

We generated a novel non-peptidic PI, GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF), which exerted potent activity against a wide spectrum of HIV-1 including multi-drug-resistant HIV-1 variants (HIV_MDR). GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates including subtypes A, B, C, and E (50% effective concentration [EC₅₀], 0.015-0.038 µM) with minimal cytotoxicity (CC₅₀: >100 µM in CD4⁺ MT-2 cells), although it was less active to two HIV-2 strains (HIV-2_EHO and HIV-2_ROD) (EC₅₀: 0.60 µM) than to HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of HIV-1_NL4-3 variants exposed to and selected by up to 5 µM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and a 1µM of lopinavir or atazanavir (EC₅₀: 0.036 - 0.14 µM). GRL-02031 was also potent against multi-PI resistance in clinical HIV-1 variants isolated from patients who had no response to then existing conventional antiretroviral regimens with EC₅₀ values ranging 0.014 - 0.042 µM (<2-fold changes in EC₅₀ values compared with that of wild-type HIV-1). Upon selection of HIV-1_NL4-3 in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24/p2 cleavage site), R409K (within p7), and I437T (p7/p1 cleavage site) in the Gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1_NL4-3-based molecular infectious clones containing a single primary mutation previously reported or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying resistance development of HIV-1 to GRL-02031. The present data warrant that GRL-02031 be further developed as a potential therapeutic agent for treatment of infection with primary and multi-drug-resistant HIV-1.