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 (Thomas Land Publishers Incorporated);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...

  • Early virological suppression despite high frequency NNRTI resistance following perinatal prophylaxis in HIV-infected African infants. Prendergast, Andrew; Mphatswe, Wendy; Tudor-Williams, Gareth; Blanckenberg, Natasha; Cengimbo, Ayanda; Jeena, Prakash; Rakgotho, Mpho; Pillay, Visva; Thobakgale, Christina; Reddy, Sharon; Mncube, Zenele; Vanderstok, Mary; McCarthy, Noel; Dong, Krista; Coovadia, Hoosen; Morris, Lynn; Walker, Bruce D.; Goulder, Philip // Retrovirology;2008 Supplement 1, Vol. 5, Special section p1 

    Background Infants infected with HIV-1 perinatally, despite single-dose nevirapine (sd-NVP) prophylaxis, progress rapidly. Furthermore, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations, following exposure to sd-NVP, may have deleterious effects on efficacy of...

  • 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...

  • Winning The Battle Against HIV-1. Secasan, Iosif; Pop, Dan I.; Secasan, Ciprian C. // Internet Journal of Infectious Diseases;2007, Vol. 6 Issue 1, p4 

    Objective: To present an entirely new theory and practical solution to completely eliminate HIV-1 from the human body, based on a combination between a HAART regimen (HAART-x) and a corresponding, pre-administrated-to-(HAART-x), therapeutic vaccine (Vaccine-x) made of short HIV-1 DNA-sequences...

  • Design Strategies of Novel NNRTIs to Overcome Drug Resistance. Peng Zhan; Xinyong Liu; Zhenyu Li; Pannecouque, Christophe; De Clercq, Erik // Current Medicinal Chemistry;Oct2009, Vol. 16 Issue 29, p3903 

    Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). However, to a great extent, the efficacy of NNRTI drugs is impaired by rapid emergence of drug-resistance mutations. Fortunately,...

  • Clinical Validation and Applicability of Different Tipranavir/Ritonavir Genotypic Scores in HIV-1 Protease Inhibitor-Experienced Patients. Saracino, Annalisa; Monno, Laura; Tartaglia, Alessandra; Tinelli, Carmine; Seminari, Elena; Maggiolo, Franco; Bonora, Stefano; Rusconi, Stefano; Micheli, Valeria; Caputo, Sergio Lo; Lazzaroni, Laura; Ferrara, Sergio; Ladisa, Nicoletta; Nasta, Paola; Parruti, Giustino; Bellagamba, Rita; Forbici, Federica; Angarano, Gioacchino // Current HIV Research;Jul2009, Vol. 7 Issue 4, p425 

    Tipranavir, a non-peptidic protease inhibitor which shows in vitro efficacy against some HIV-1-resistant strains, can be used in salvage therapies for multi-experienced HIV patients due to its peculiar resistance profile including 21 mutations at 16 protease positions according to International...


Read the Article


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

Try another library?
Sign out of this library

Other Topics