GRL-079, a novel P2-Tp-THF-C5-alkylamine- and P2 -Abt-containing HIV-1 protease inhibitor, is extremely potent against multi-drug-resistant HIV-1 variants including HIVDRVRp51 and has a high genetic barrier against the emergence of resistant variants [PublishAheadOfPrint]

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-1_NL4-3, 0.3-6.7 nM against HIV-2_EHO, and 0.9-90 nM against laboratory-selected-PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIV_MDR). GRL-078, -079, -077, and -058 also effectively blocked the replication of HIV-1 variants highly resistant to darunavir (DRV:HIV_DRV^R_p51), 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 HIV_DRV^R_p51. 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 HIV_MDR strains (HIV_11MIX), HIV_11MIX became highly resistant to LPV and DRV over 13-32 and 32-41 weeks, respectively. However, when selected with GRL-079 and GRL-058, HIV_11MIX 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-1_NL4-3 and a wide spectrum of HIV_MDRs.

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