Structure-function studies of multidrug-resistant HIV-1 protease in complex with darunavir

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NCI	STRUCTBIO-11

Authors

• R Yedidi
• K Maeda
• D Davis
• D Das
• P Wingfield
• D Smith
• H Mitsuya

Abstract

Darunavir (DRV), a recently FDA-approved HIV-1 protease inhibitor, exerts potent activity against both wild-type and multidrug-resistant human immunodeficiency virus type-1 (HIV) strains. The current study focuses on understanding the binding of DRV to HIV protease, derived from a clinical isolate, HIVMDR, that contains eight amino acid substitutions (L10I, K45R, I54V, L63P, A71V, V82T, L90M and I93L) in the protease sequence. MTT-based assays were performed using human MT4 cells exposed to HIV and cultured in the presence of DRV or other protease inhibitors. Antiviral data showed that DRV is 50-to 100-fold potent (IC50 1-2 nM) against HIVMDR, compared to other inhibitors tested. Crystal structure of HIVMDR protease in complex with DRV was solved and analyzed. The overall orientation of DRV binding to HIVMDR protease did not significantly change compared to that to wild-type HIV protease. DRV bound to HIVMDR protease in two orientations with a bridging water molecule to the flaps. The bis-THF and aniline moieties were involved in two and one polar contacts, respectively, with the HIVMDR protease backbone. DRV also had altered but persistent hydrophobic contacts with HIVMDR protease. Thus, the crystal structure of HIVMDR protease in complex with DRV supports the antiviral potency of DRV against HIVMDR.

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