GRL-02031, a Novel Nonpeptidic Protease Inhibitor (PI) Containing a Stereochemically Defined Fused Cyclopentanyltetrahydrofuran Potent against Multi-PI-Resistant Human Immunodeficiency Virus Type 1 In Vitro

Article

Author: Nakata, Hirotomo ; Das, Debananda ; Leschenko, Sofiya ; Ogata-Aoki, Hiromi ; Koh, Yasuhiro ; Nakayama, Maki ; Ghosh, Arun K. ; Mitsuya, Hiroaki ; Amano, Masayuki

ABSTRACT We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC 50 ] range, 0.015 to 0.038 μM), with minimal cytotoxicity (50% cytotoxic concentration, >100 μM in CD4 + MT-2 cells), although it was less active against two HIV-2 strains (HIV-2 EHO and HIV-2 ROD ) (EC 50 , ∼0.60 μM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1 NL4-3 variants exposed to and selected by up to 5 μM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 μM of lopinavir or atazanavir (EC 50 range, 0.036 to 0.14 μM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC 50 s ranging from 0.014 to 0.042 μM (changes in the EC 50 s were less than twofold the EC 50 for 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 reported previously 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 the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Preclinical	JP	Kumamoto University	01 Mar 2009

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