Journal article
Effect of mimetic CDK9 inhibitors on HIV-1 activated transcription
Journal of molecular biology, Vol.425(4), pp.812-829
02/22/2013
DOI: 10.1016/j.jmb.2012.12.005
PMCID: PMC3595178
PMID: 23247501
Abstract
Potent antiretroviral therapy (ART) has transformed HIV-1 infection into a chronic manageable disease; however drug resistance remains a common problem that limits the effectiveness and clinical benefits of this type of treatment. The discovery of viral reservoirs in the body, in which HIV-1 may persist, has helped to explain why therapeutic eradication of HIV-1 has proved so difficult. In the current study we utilized a combination of structure based analysis of Cyclin/CDK complexes with our previously published Tat peptide derivatives. We modeled the Tat peptide inhibitors with CDKs and found a particular pocket which showed the most stable binding site (Cavity 1) using
in silico
analysis. Furthermore, we were able to find peptide mimetics that bound to similar regions using
in silico
searches of a chemical library, followed by cell based biological assays. Using these methods we obtained the first generation mimetic drugs and tested these compounds on HIV-1 LTR activated transcription. Using biological assays followed by similar
in silico
analysis to find a 2
nd
generation drugs resembling the original mimetic, we found the new targets of Cavity 1 and Cavity 2 regions on CDK9. We examined the 2
nd
generation mimetic against various viral isolates, and observed a generalized suppression of most HIV-1 isolates. Finally, the drug inhibited viral replication in humanized mouse models of Rag2
-/-
γc
-/-
with no toxicity to the animals at tested concentrations. Our results suggest that it may be possible to model peptide inhibitors into available crystal structures and further find drug mimetics using
in silico
analysis.
Details
- Title: Subtitle
- Effect of mimetic CDK9 inhibitors on HIV-1 activated transcription
- Creators
- Rachel Van Duyne - George Mason University, National Center for Biodefense & Infectious Diseases, Manassas, VA 20110, USAIrene Guendel - George Mason University, National Center for Biodefense & Infectious Diseases, Manassas, VA 20110, USAElizabeth Jaworski - George Mason University, National Center for Biodefense & Infectious Diseases, Manassas, VA 20110, USAGavin Sampey - George Mason University, National Center for Biodefense & Infectious Diseases, Manassas, VA 20110, USAZachary Klase - Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0460, USAHao Chen - The George Washington University, Department of Physics, Washington, District of Columbia 20052, USAChen Zeng - The George Washington University, Department of Physics, Washington, District of Columbia 20052, USADmytro Kovalskyy - Institute of Molecular Biology and Genetics, Protein Engineering Department, UAS, Kiev, UkraineMahmoud H el Kouni - University of Alabama at Birmingham, Department of Pharmacology and Toxicology, Comprehensive Cancer Center, Center for Aids Research, Birmingham, AL, 35294, USABenjamin Lepene - Ceres Nanosciences, Inc., Manassas, VA 20110Alexis Patanarut - Ceres Nanosciences, Inc., Manassas, VA 20110Sergei Nekhai - Howard University, Center for Sickle Cell Disease, Department of Medicine, Washington, DC 20060, USADavid H Price - Department of Biochemistry, Interdisciplinary Molecular Biology Program, University of Iowa, Iowa City, IA, USAFatah Kashanchi - George Mason University, National Center for Biodefense & Infectious Diseases, Manassas, VA 20110, USA
- Resource Type
- Journal article
- Publication Details
- Journal of molecular biology, Vol.425(4), pp.812-829
- DOI
- 10.1016/j.jmb.2012.12.005
- PMID
- 23247501
- PMCID
- PMC3595178
- NLM abbreviation
- J Mol Biol
- ISSN
- 0022-2836
- eISSN
- 1089-8638
- Grant note
- SC1 GM082325 || GM / National Institute of General Medical Sciences : NIGMS G12 RR003048 || RR / National Center for Research Resources : NCRR P30 HL107253 || HL / National Heart, Lung, and Blood Institute : NHLBI
- Language
- English
- Date published
- 02/22/2013
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984025292202771
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