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Antimicrobial Agents and Chemotherapy, September 2005, p. 3825-3832, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3825-3832.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Molecular Basis for Increased Susceptibility of Isolates with Atazanavir Resistance-Conferring Substitution I50L to Other Protease Inhibitors

Joseph Yanchunas Jr.,1 David R. Langley,2 Li Tao,1 Ronald E. Rose,3 Jacques Friborg,3 Richard J. Colonno,3 and Michael L. Doyle1*

Departments of Gene Expression and Protein Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Route 206 and Province Line Road, Princeton, New Jersey 08543-4000,1 Computer-Aided Drug Design,2 Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492-76603

Received 17 February 2005/ Returned for modification 19 April 2005/ Accepted 16 June 2005

Protease inhibitors (PIs) are highly effective drugs against the human immunodeficiency virus (HIV), yet long-term therapeutic use is limited by emergence of HIV type 1 (HIV-1) protease substitutions that confer cross-resistance to multiple protease inhibitor drugs. Atazanavir is a highly potent HIV protease inhibitor with a distinct resistance profile that includes effectiveness against most HIV-1 isolates resistant to one or two PIs. The signature resistance substitution for atazanavir is I50L, and it is frequently (53%) accompanied by a compensatory A71V substitution that helps restore viability and increases atazanavir resistance levels. We measured the binding affinities of wild-type (WT) and I50L/A71V HIV-1 proteases to atazanavir and other currently approved PIs (ritonavir, lopinavir, saquinavir, nelfinavir, indinavir, and amprenavir) by isothermal titration calorimetry. Remarkably, we find that all of the PIs have 2- to 10-fold increased affinities for I50L/A71V protease, except for atazanavir. The results are also manifested by thermal stability measures of affinity for WT and I50L/A71V proteases. Additional biophysical and enzyme kinetics experiments show I50L/A71V protease is a stable enzyme with catalytic activity that is slightly reduced (34%) relative to the WT. Computational modeling reveals that the unique resistance phenotype of I50L/A71V protease likely originates from bulky tert-butyl groups at P2 and P2' (specific to atazanavir) that sterically clash with methyl groups on residue L50. The results of this study provide a molecular understanding of the novel hypersusceptibility of atazanavir-resistant I50L/A71V-containing clinical isolates to other currently approved PIs.

* Corresponding author. Mailing address: Gene Expression and Protein Biochemistry Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000. Phone: (609) 252-3175. Fax: (609) 252-6012. E-mail: michael.doyle{at}bms.com.

Antimicrobial Agents and Chemotherapy, September 2005, p. 3825-3832, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3825-3832.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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