Kovalevsky, Andrey Y Liu, Fengling Leshchenko, Sofiya Ghosh, Arun K Louis, John M Harrison, Robert W Weber, Irene T
Published in
Journal of molecular biology
TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for treatment of drug resistant HIV/AIDS. We report the ultra-high 0.84 A resolution crystal structure of the TMC114 complex with PR containing the drug-resistant mutation V32I (PR(V32I)), and the 1.22 A resolution structure of a complex with PR(M46L). These structures show...
Hoetelmans, Richard M W Mariën, Kris De Pauw, Martine Hill, Andrew Peeters, Monika Sekar, Vanitha De Doncker, Piet Woodfall, Brian Lefebvre, Eric
Published in
British journal of clinical pharmacology
The interaction between TMC114/r and tenofovir is not clinically relevant and no dose adjustments are required when these drugs are coadministered.
Ghosh, Arun K Dawson, Zachary L Mitsuya, Hiroaki
Published in
Bioorganic & medicinal chemistry
Our structure-based design strategies which specifically target the HIV-1 protease backbone, resulted in a number of exceedingly potent nonpeptidyl inhibitors. One of these inhibitors, darunavir (TMC114), contains a privileged, structure-based designed high-affinity P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF). Darunavir has ...
Hudon, Sarah E. Coffinier, Catherine Michaelis, Susan Fong, Loren G. Young, Stephen G. Hrycyna, Christine A.
Published in
Biochemical and Biophysical Research Communications
We reported that several HIV protease inhibitors (HIV-PIs) interfere with the endoproteolytic processing of two farnesylated proteins, yeast a-factor and mammalian prelamin A. We proposed that these drugs interfere with prelamin A processing by blocking ZMPSTE24, an integral membrane zinc metalloproteinase known to play a critical role in its proce...
Sekar, Vanitha J Lefebvre, Eric De Pauw, Martine Vangeneugden, Tony Hoetelmans, Richard M
Published in
British journal of clinical pharmacology
The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day(-1) is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.
Hou, Tingjun McLaughlin, William A Wang, Wei
Published in
Proteins
HIV-1 protease has been an important drug target for the antiretroviral treatment of HIV infection. The efficacy of protease drugs is impaired by the rapid emergence of resistant virus strains. Understanding the molecular basis and evaluating the potency of an inhibitor to combat resistance are no doubt important in AIDS therapy. In this study, we ...
Lascar, R Monica Benn, Paul
Published in
HIV/AIDS (Auckland, N.Z.)
There is an ongoing need for potent antiretroviral therapies to deal with the increasing pool of treatment-experienced patients with multiple drug resistance. The last few years have seen the arrival of 2 new and very potent protease inhibitors - darunavir and tipranavir - alongside 2 whole new classes of anti-HIV agents - the integrase inhibitors ...
Wolfe, Cameron Hicks, Charles
Published in
HIV/AIDS (Auckland, N.Z.)
Darunavir (formerly TMC114) is a second-generation, sulfonamide-based, peptidomimetic protease inhibitor (PI) with a modified 3-dimensional structure enabling more efficient binding to HIV protease. It has become an important drug, in combination with low-dose ritonavir boosting, in the treatment of both antiretroviral-naïve and multiclass-experien...
Weber, Irene T Agniswamy, Johnson
Published in
Viruses
Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. Th...
Rosso, R Bernardini, C Bruzzone, B Secondo, G Icardi, G Viscoli, C Di Biagio, A
Published in
European Journal of Medical Research
Multiclass-drug resistance, often caused by poor treatment compliance, is a challenging problem in all categories of HIV-infected patients. Selective pressure is higher in youth for both biological and behavioral reasons. We report the case of a 15-year-old Caucasian male, with vertically acquired HIV-1 infection, who failed several lines of antire...
