3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

CRYSTALLOGRAPHIC STUDY WITH BILR 355 BS, A NOVEL NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) WITH A BROAD ANTI HIV-1 PROFILE

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. WePp0105

Coulombe R., Fink D., Landry S., Lessard I.A.D., McCollum R., Naud J., O'Meara J., Simoneau B., Yoakim C., Bonneau P.R.
Boehringer Ingelheim (Canada) Ltd, Laval, Canada

INTRODUCTION: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are potent components of combination antiretroviral therapies. However patients failing on an NNRTI-containing regimen typically select for viruses that are cross-resistant to all members of the class, leaving them with no further NNRTI options. Following extensive structure-activity relationship studies we have identified BILR 355 BS, a novel NNRTI with potent antiviral activity against clinically prevalent NNRTI-resistant variants. The objective of this work is to better understand the interactions made by BILR 355 BS through X-ray crystallography with wild-type and mutant RT enzymes.

METHODS: The RT proteins were produced in E. coli from coexpression of differentially tagged p66 and p51 constructs followed by affinity purification. High quality diffracting crystals were then obtained using novel crystallization conditions with wild-type and mutant RT enzymes (incl. K103N, Y181C and K103N/Y181C) complexed with BILR 355 BS and two related analogues.

RESULTS: The excellent diffraction data (2.7-2.1Å resolution) allowed for a detailed analysis of inhibitor binding modes. Superposition of the various structures reveals that while the dipyridodiazepinone core of BILR 355 BS and its analogues binds in an overall similar manner to that of nevirapine, it has a greater ability to adapt its orientation in the binding pocket of the mutants. Moreover new interactions provided by the extension at position C8 (incl. Pro 236 and Lys 103 backbone) allow these molecules to maintain potency despite the loss of interactions with the aromatic ring of Tyr181. Finally, the structure models presented here strongly support the suggestion that the entrance to the NNRTI pocket is located near the Pro 236 and Val 106 of the p66 subunit.

CONCLUSIONS: BILR 355 BS achieves a superior antiviral profile against NNRTI-resistant RTs through specific modifications to the core substitution pattern that make additional favorable binding interactions with both mutant and wild-type RTs. BILR 355 BS is currently in clinical trials.

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050724
Basic | WePp0105 | René Coulombe
New Antiretroviral Targets And Compounds, Mechanisms Of Drug Resistance

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