GRL-0519, a novel HIV-1 protease inhibitor, has potent activity against a highly darunavir-resistant strain of HIV-1

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NCI	VIROL-10

Authors

• R. S. Yedidi
• K. Maeda
• V. R. Kalapala
• D. A. Davis
• D. Das
• A. K. Ghosh
• H. Mitsuya

Abstract

In the present study, we demonstrate that GRL-0519, a novel human immunodeficiency virus type-1 (HIV-1) protease inhibitor (PI) exerts potent inhibition of a highly darunavir (DRV, an FDA-approved PI)-resistant strain of HIV-1 that was selected over 51 passages with DRV (HIVDRVRP51). GRL-0519 and DRV contain tris-tetrahydrofuran (THF) and bis-THF as P2 functional groups, respectively. The P2' functional groups for GRL-0519 and DRV are methoxybenzene and aminobenzene, respectively. Antiviral assays using human MT-4 cells show that the half-maximal effective concentration (EC50) of GRL-0519 against HIVDRVRP51 is 0.23 μM while DRV failed to inhibit the replication of HIVDRVRP51 at up to 1 μM. TMC-126, an analog of DRV that contains P2-bis-THF and P2'-methoxybenzene moieties was able to inhibit the replication of HIVDRVRP51 with an EC50 of 0.87 μM while amprenavir (APV, an FDA-approved PI), which contains P2-mono-THF and P2'-aminobenzene failed to inhibit the replication of HIVDRVRP51 at up to 1 μM. Crystallization trials for the X-ray crystallographic analysis of protease from HIVDRVRP51 (PRDRVRP51) in complex with GRL-0519 are currently in progress.

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