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Published online before print June 3, 2005, 10.1110/ps.051347405
Protein Science (2005), 14:1870-1878. Published by Cold Spring Harbor Laboratory Press. Copyright © 2005 The Protein Society
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Structural analysis of an HIV-1 protease I47A mutant resistant to the protease inhibitor lopinavir

Ron M. Kagan1, Mark D. Shenderovich2, Peter N.R. Heseltine1 and Kal Ramnarayan2

1 Department of Infectious Diseases, Quest Diagnostics Inc., San Juan Capistrano, California 92675, USA
2 Cengent Therapeutics Inc., San Diego, California 92127, USA

(RECEIVED January 10, 2005; FINAL REVISION April 10, 2005; ACCEPTED April 11, 2005)

We have identified a rare HIV-1 protease (PR) mutation, I47A, associated with a high level of resistance to the protease inhibitor lopinavir (LPV) and with hypersusceptibility to the protease inhibitor saquinavir (SQV). The I47A mutation was found in 99 of 112,198 clinical specimens genotyped after LPV became available in late 2000, but in none of 24,426 clinical samples genotyped from 1998 to October 2000. Phenotypic data obtained for five I47A mutants showed unexpected resistance to LPV (86- to >110-fold) and hypersusceptibility to SQV (0.1- to 0.7-fold). Molecular modeling and energy calculations for these mutants using our structural phenotyping methodology showed an increase in the binding energy of LPV by 1.9–3.1 kcal/mol with respect to the wild type complex, corresponding to a 20- to >100-fold decrease in binding affinity, consistent with the observed high levels of LPV resistance. In the WT PR–LPV complex, the Ile 47 side chain is positioned close to the phenoxyacetyl moiety of LPV and its van der Waals interactions contribute significantly to the ligand binding. These interactions are lost for the smaller Ala 47 residue. Calculated binding energy changes for SQV ranged from –0.4 to –1.2 kcal/mol. In the mutant I47A PR–SQV complexes, the PR flaps are packed more tightly around SQV than in the WT complex, resulting in the formation of additional hydrogen bonds that increase binding affinity of SQV consistent with phenotypic hypersusceptibility. The emergence of mutations at PR residue 47 strongly correlates with increasing prescriptions of LPV (Spearman correlation rs=0.96, P<.0001).

Keywords: HIV protease inhibitors; lopinavir; saquinavir; drug resistance; molecular modeling; binding energy; structure-based phenotyping

Abbreviations: 3D, three-dimensional • HIV-1, human immunodeficiency virus type 1 • ARV, anti-retroviral • APV, amprenavir • IDV, indinavir • LPV, lopinavir • LPV/r, lopinavir coadministered with ritonavir • NFV, nelfinavir • SQV, saquinavir • PI, protease inhibitor • PR, protease • WT, wild type.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051347405.

Reprint requests to: Ron M. Kagan, Department of Infectious Diseases, Quest Diagnostics Inc., 33608 Ortega Highway, San Juan Capistrano, CA 92675, USA; e-mail: kaganr{at}questdiagnostics.com; fax: (949) 728-4022.


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