X-ray crystallographic structure of ABT-378 (Lopinavir) bound to HIV-1 protease

Stoll, V.S.; Qin, Wenying; Stewart, Kent D.; Jakob, C.G.; Park, Chang; Walter, Karl A.; Simmer, Robert L.; Helfrich, Rosalind; Bussiere, Dirk; Kao, James; Kempf, Dale J.; Sham, Hing L.; Norbeck, Daniel W.

doi:10.1016/s0968-0896(02)00051-2

Cited by 97 publications

(85 citation statements)

References 16 publications

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“…Our X-ray crystallographic analysis of the two inhibitor complexes of the MDR HIV-1 protease indicates structural changes in several areas. Neither lopinavir nor DMP450 binds to MDR isolate 769 HIV-1 protease in the same way as these two protease inhibitors bind to the wild-type HIV-1 protease (19,48) (Fig. 3 and 5).…”

Section: Discussionmentioning

confidence: 95%

“…Many mutations in the protease and reverse transcriptase genes of HIV-1 have been associated with antiretroviral drug resistance (40). Protease inhibitor resistance mutations have been reported at codons 10,20,24,30,32,33,36,46,47,48,50,53,54,63,71,73,77,82,84, and 90 (5). Certain single mutations or combinations of point mutations confer cross-resistance to several protease inhibitors (40).…”

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confidence: 99%

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Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

Logsdon¹,

Vickrey²,

Martin³

et al. 2004

J Virol

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

Logsdon¹,

Vickrey²,

Martin³

et al. 2004

J Virol

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“…Residues 32 and 47 occupy adjacent positions in the symmetry-related S2 and S2Ј subsites of the HIV PR active site. The P2 isopropyl group and the terminal dimethylphenoxy moiety of LPV are in van der Waals contact with the side chains of isoleucine 47 and 47Ј (37). Evolution of I47V to I47A creates a small but significant amount of unoccupied volume, decreasing the van der Waals interaction and lowering the affinity of the drug for the PR active site (5).…”

Section: Discussionmentioning

confidence: 99%

Selection of Resistance in Protease Inhibitor-Experienced, Human Immunodeficiency Virus Type 1-Infected Subjects Failing Lopinavir- and Ritonavir-Based Therapy: Mutation Patterns and Baseline Correlates

King

et al. 2005

J Virol

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The selection of in vivo resistance to lopinavir was characterized by analyzing the longitudinal isolates from 54 protease inhibitor-experienced subjects who either experienced incomplete virologic response or viral rebound subsequent to initial response while on treatment with lopinavir-ritonavir in Phase II and III studies. The evolution of incremental resistance to lopinavir (emergence of new mutation [s] and/or at least a twofold increase in phenotypic resistance compared to baseline isolates) was highly dependent on the baseline phenotype and genotype. Among the subjects demonstrating evolution of lopinavir resistance, mutations at positions 82, 54, and 46 in human immunodeficiency virus protease emerged frequently, suggesting that these mutations are important for conferring high-level resistance. Less common mutations, such as L33F, I50V, and V32I together with I47V/A, were also selected; however, new mutations at positions 84, 90, and 71 were not observed. The emergence of incremental resistance contrasts greatly with the low incidence of resistance observed after initiating lopinavir-ritonavir therapy in antiretroviral-naive patients, suggesting that partial resistance accumulated during prior protease inhibitor therapy can compromise the genetic barrier to resistance to lopinavir-ritonavir. The emergence of incremental resistance was uncommon in subjects whose baseline isolates contained eight or more mutations associated with lopinavir resistance and/or displayed >60-fold-reduced susceptibility to lopinavir, providing insight into suitable upper genotypic and phenotypic breakpoints for lopinavir-ritonavir.

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“…The Protein Design module within QUANTA (Accelrys Corporation, San Diego, CA) was used to overlay the HIV PR/drug complexes and to insert the I50L substitution into the PR structure. The x-ray structures used in this study [capsid-p2, 1f7a (17a); IDV, 1hsg (4); LPV, 1mui (25); NFV, 1ohr (12); RTV, 1hxw (13); SQV, 1mtb (10); APV, 1hpv (22a)] were obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (PDB) (1) with the exception of the ATV structure (H. E. Klei, K. Kish, P.-F. Lin, Q. Guo, J. Friborg, R. E. Rose, Y. Zhang, V. Goldfarb, M. G. Wittekind, and S. Sheriff, unpublished data). The inhibitor structures were overlaid onto the capsid-p2 structure.…”

Section: Methodsmentioning

confidence: 99%

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

Yanchunas

Langley

Tao

et al. 2005

Antimicrob Agents Chemother

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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.

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X-ray crystallographic structure of ABT-378 (Lopinavir) bound to HIV-1 protease

Cited by 97 publications

References 16 publications

Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

Selection of Resistance in Protease Inhibitor-Experienced, Human Immunodeficiency Virus Type 1-Infected Subjects Failing Lopinavir- and Ritonavir-Based Therapy: Mutation Patterns and Baseline Correlates

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

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