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X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir ^,

Herbert E. Klei,^1* Kevin Kish,¹ Pin-Fang M. Lin,⁵ Qi Guo,^5,6 Jacques Friborg,⁵ Ronald E. Rose,⁵ Yaqun Zhang,^2,3 Valentina Goldfarb,² David R. Langley,⁴ Michael Wittekind,^2,3, and Steven Sheriff¹

Macromolecular Crystallography,¹ Macromolecular NMR,² Gene Expression & Protein Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000,³ Computer Assisted Drug Design,⁴ Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660,⁵ Applied Genomics, Bristol-Myers Squibb Pharmaceutical Research Institute, Hopewell, New Jersey 08534-2130⁶

Received 30 November 2005/ Accepted 22 May 2007

Atazanavir, which is marketed as REYATAZ, is the first human immunodeficiency virus type 1 (HIV-1) protease inhibitor approved for once-daily administration. As previously reported, atazanavir offers improved inhibitory profiles against several common variants of HIV-1 protease over those of the other peptidomimetic inhibitors currently on the market. This work describes the X-ray crystal structures of complexes of atazanavir with two HIV-1 protease variants, namely, (i) an enzyme optimized for resistance to autolysis and oxidation, referred to as the cleavage-resistant mutant (CRM); and (ii) the M46I/V82F/I84V/L90M mutant of the CRM enzyme, which is resistant to all approved HIV-1 protease inhibitors, referred to as the inhibitor-resistant mutant. In these two complexes, atazanavir adopts distinct bound conformations in response to the V82F substitution, which may explain why this substitution, at least in isolation, has yet to be selected in vitro or in the clinic. Because of its nearly symmetrical chemical structure, atazanavir is able to make several analogous contacts with each monomer of the biological dimer.

Published ahead of print on 30 May 2007.

Supplemental material for this article may be found at http://jvi.asm.org/.

Present address: Amgen, 1201 Amgen Court West, Seattle, WA 98119-3105.

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