We identified four novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-078, -079, -077, and -058, containing an alkylamine at the C5 position of P2-tetrahydropyrano-tetrahydrofuran (Tp-THF) and a P2' -cyclopropyl (Cp)(or isopropyl)-aminobenzothiazole (Abt). Their 50% effective concentrations (EC50s) were 2.5-30 nM against wild-type HIV-1NL4-3, 0.3-6.7 nM against HIV-2EHO, and 0.9-90 nM against laboratory-selected-PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIVMDR). GRL-078, -079, -077, and -058 also effectively blocked the replication of HIV-1 variants highly resistant to darunavir (DRV:HIVDRVRp51), with EC50 values of 38, 62, 61, and 90 nM, respectively, while four FDA-approved PIs examined [amprenavir, atazanavir, lopinavir (LPV), and DRV] virtually had no activity (EC50>1,000 nM) against HIVDRVRp51. Structurally, GRL-078, -079, and -058 form strong hydrogen bond interactions between the C5-modified-Tp-THF and Asp29/Asp30/Gly48 of wild-type protease while P2' -Cp-Abt forms strong hydrogen bonds with Asp30' . The Tp-THF and Cp-Abt moieties also have good nonpolar interactions with protease residues located in the flap region. When selected with LPV and DRV using a mixture of 11 HIVMDR strains (HIV11MIX), HIV11MIX became highly resistant to LPV and DRV over 13-32 and 32-41 weeks, respectively. However, when selected with GRL-079 and GRL-058, HIV11MIX failed to replicate at >0.08 μM and >0.2 μM, respectively. Thermal stability results supported the highly favorable anti-HIV-1 potency of GRL-079 as well as other PIs. The present data strongly suggest that the C5-modified P2-Tp-THF and P2' -Abt moiety contribute to the potent anti-HIV-1 profiles of the four PIs against HIV-1NL4-3 and a wide spectrum of HIVMDRs.
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