Significant increase in the potency by bis-tetrahydrofuran (THF) and tris-THF moieties as P2 functional groups of HIV-1 protease inhibitors against a clinical isolate (A02) HIV-1 protease

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	STRUCTBIO-10

Authors

• R.S. Yedidi
• K. Maeda
• D.A. Davis
• D. Das
• J.D. Kaufman
• S.J. Stahl
• P. Wingfield
• D.W. Smith
• V. Kalapala
• A.K. Ghosh
• H. Mitsuya

Abstract

GRL-0519, a novel human immunodeficiency virus type-1 (HIV-1) protease inhibitor (PI) exhibits higher potency than darunavir (DRV), an FDA-approved PI, against both wild type (NL4-3) and multi-drug-resistant (MDR) HIV-1 strains. GRL-0519, DRV, and amprenavir (APV) consist of tris-THF (tetrahydrofuran), bis-THF, and mono-THF moieties as P2 functional groups respectively. GRL-0519, DRV and APV were evaluated against an MDR clinical HIV-1 isolate, containing substitutions L10I, K45R, I54V, L63P, A71V, V82T, L90M, and I93L. GRL-0519 (IC50: 0.7 nM) was 2- and >200-fold more potent against MDR HIV-1 compared to DRV and APV respectively. Crystal structures of MDR protease revealed that all three compounds showed consistent direct polar contacts with the backbone amide nitrogen/carbonyl oxygen atoms of D29, D30, and D30'. The mono-THF moiety of APV showed two contacts while the bis-THF and tris-THF moieties showed three contacts (two with D29 and one with D30) suggesting that both DRV and GRL-0519 have relatively a firmer grip on MDR protease in the S2 binding pocket compared to APV. GRL-0519 showed maximum contacts amongst, supporting its high antiviral potency. Thus, the bis-THF and tris-THF moieties significantly boost the potency of DRV and GRL-0519 respectively explaining their better inhibition profiles compared to that of APV.

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