Dynamical Basis for Drug Resistance of HIV-1 Protease

Yi Mao
January 2011
BMC Structural Biology;2011, Vol. 11 Issue 1, p31
Academic Journal
Background: Protease inhibitors designed to bind to protease have become major anti-AIDS drugs. Unfortunately, the emergence of viral mutations severely limits the long-term efficiency of the inhibitors. The resistance mechanism of these diversely located mutations remains unclear. Results: Here I use an elastic network model to probe the connection between the global dynamics of HIV-1 protease and the structural distribution of drug-resistance mutations. The models for study are the crystal structures of unbounded and bound (with the substrate and nine FDA approved inhibitors) forms of HIV-1 protease. Coarsegrained modeling uncovers two groups that couple either with the active site or the flap. These two groups constitute a majority of the drug-resistance residues. In addition, the significance of residues is found to be correlated with their dynamical changes in binding and the results agree well with the complete mutagenesis experiment of HIV-1 protease. Conclusions: The dynamic study of HIV-1 protease elucidates the functional importance of common drugresistance mutations and suggests a unifying mechanism for drug-resistance residues based on their dynamical properties. The results support the robustness of the elastic network model as a potential predictive tool for drug resistance.


Related Articles

  • Structural and Thermodynamic Basis of Resistance to HIV-1 Protease Inhibition: Implications for Inhibitor Design. Velazquez-Campoy, Adrian; Muzammil, Salman; Ohtaka, Hiroyasu; Schön, Arne; Vega, Sonia; Feire, Ernesto // Current Drug Targets - Infectious Disorders;Dec2003, Vol. 3 Issue 4, p311 

    One of the most serious side effects associated with the therapy of HIV-1 infection is the appearance of viral strains that exhibit resistance to protease inhibitors. At the molecular level, resistance to protease inhibition predominantly takes the form of mutations within the protease molecule...

  • Impact of the Background Regimen on Virologic Response to Etravirine: Pooled 48-Week Analysis of DUET-1 and -2. Trottier, Benoit; Di Perri, Giovanni; Madruga, José Valdez; Peeters, Monika; Vingerhoets, Johan; Picchio, Gaston; Woodfall, Brian J. // HIV Clinical Trials;Jul/Aug2010, Vol. 11 Issue 4, p175 

    Purpose: This subgroup analysis of the phase 3 DUET trials examined the impact of the background regimen on virologic response to etravirine in treatment-experienced patients. Methods: Patients received etravirine 200 mg or placebo, both twice daily with a background regimen of...

  • Genetic Consequences of Antiviral Therapy on HIV-1. Arenas, Miguel // Computational & Mathematical Methods in Medicine;6/10/2015, Vol. 2015, p1 

    A variety of enzyme inhibitors have been developed in combating HIV-1, however the fast evolutionary rate of this virus commonly leads to the emergence of resistance mutations that finally allows the mutant virus to survive. This review explores the main genetic consequences of HIV-1 molecular...

  • Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Juric, Dejan; Castel, Pau; Griffith, Malachi; Griffith, Obi L.; Won, Helen H.; Ellis, Haley; Ebbesen, Saya H.; Ainscough, Benjamin J.; Ramu, Avinash; Iyer, Gopa; Shah, Ronak H.; Huynh, Tiffany; Mino-Kenudson, Mari; Sgroi, Dennis; Isakoff, Steven; Thabet, Ashraf; Elamine, Leila; Solit, David B.; Lowe, Scott W.; Quadt, Cornelia // Nature;2/12/2015, Vol. 518 Issue 7538, p240 

    Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided...

  • WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors. Anastas, Jamie N.; Kulikauskas, Rima M.; Tamir, Tigist; Rizos, Helen; Long, Georgina V.; von Euw, Erika M.; Pei-Tzu Yang; Hsiao-Wang Chen; Haydu, Lauren; Toroni, Rachel A.; Lucero, Olivia M.; Chien, Andy J.; Moon, Randall T. // Journal of Clinical Investigation;Jul2014, Vol. 124 Issue 7, p2877 

    About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAFV600E/K) that can be selectively inhibited by targeted BRAF inhibitors (BFLAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of...

  • Dasatinib May Override F317L BCR-ABL Kinase Domain Mutation in Patients with Chronic Myeloid Leukemia. Eşkazan, Ahmet Emre; Soysal, Teoman // Turkish Journal of Hematology;Jun2013, Vol. 30 Issue 2, p211 

    A letter to the editor is presented which is concerned with research which found that the drug dasatinib may override F317L BCR-ABL kinase domain mutation in patients with chronic myeloid leukemia.

  • Iclusig: A New Treatment Option for Adults with CML or Ph+ ALL that Is Resistant/ Intolerant to Previous Therapy with TKIs. Lederman, Lynne // American Health & Drug Benefits;Apr2013, Vol. 6 Issue 3, p77 

    The article discusses the Food and Drug Administration (FDA) approval in December 2012 for ponatinib in iclusig from Ariad Pharmaceuticals for adult patients with accelerated-phase (AP), chronic-phase (CP) and blast-phase (BP) acute lymphomatic leukemia (ALL) and chronic myeloid leukemia (CML)....

  • RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Poulikakos, Poulikos I.; Zhang, Chao; Bollag, Gideon; Shokat, Kevan M.; Rosen, Neal // Nature;3/18/2010, Vol. 464 Issue 7287, p427 

    Tumours with mutant BRAF are dependent on the RAF–MEK–ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the...

  • The Role of Irreversible HER Family Inhibition in the Treatment of Patients with Non-Small Cell Lung Cancer. KWAK, EUNICE // Oncologist;Nov2011, Vol. 16 Issue 11, p1498 

    Small-molecule tyrosine kinase inhibitors (TKIs) of the human epidermal growth factor receptor (HER) include the reversible epidermal growth factor receptor (EGFR/ HER-1) inhibitors gefitinib and erlotinib. EGFR TKIs have demonstrated activity in the treatment of patients with non-small cell...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics