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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Amiralaei, Sheida Anderson, Karen S. Sohl, Christal D. Yin, Y. Whitney Mislak, Andrea C. Schinazi, Raymond F. Shumate, Christie K. Szymanski, Michal R. |
| Description | Author Affiliation: Sohl CD ( Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520); Szymanski MR ( Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555); Mislak AC ( Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520); Shumate CK ( Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555); Amiralaei S ( Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322); Schinazi RF ( Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322); Anderson KS ( Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520); Yin YW ( Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555); |
| Abstract | Nucleoside analog reverse transcriptase inhibitors (NRTIs) are the essential components of highly active antiretroviral (HAART) therapy targeting HIV reverse transcriptase (RT). NRTI triphosphates (NRTI-TP), the biologically active forms, act as chain terminators of viral DNA synthesis. Unfortunately, NRTIs also inhibit human mitochondrial DNA polymerase (Pol γ), causing unwanted mitochondrial toxicity. Understanding the structural and mechanistic differences between Pol γ and RT in response to NRTIs will provide invaluable insight to aid in designing more effective drugs with lower toxicity. The NRTIs emtricitabine [(-)-2,3'-dideoxy-5-fluoro-3'-thiacytidine, (-)-FTC] and lamivudine, [(-)-2,3'-dideoxy-3'-thiacytidine, (-)-3TC] are both potent RT inhibitors, but Pol γ discriminates against (-)-FTC-TP by two orders of magnitude better than (-)-3TC-TP. Furthermore, although (-)-FTC-TP is only slightly more potent against HIV RT than its enantiomer (+)-FTC-TP, it is discriminated by human Pol γ four orders of magnitude more efficiently than (+)-FTC-TP. As a result, (-)-FTC is a much less toxic NRTI. Here, we present the structural and kinetic basis for this striking difference by identifying the discriminator residues of drug selectivity in both viral and human enzymes responsible for substrate selection and inhibitor specificity. For the first time, to our knowledge, this work illuminates the mechanism of (-)-FTC-TP differential selectivity and provides a structural scaffold for development of novel NRTIs with lower toxicity. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 28 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | DNA-Directed DNA Polymerase Metabolism Mitochondria Drug Effects Crystallography, X-Ray Chemistry Kinetics Enzymology Molecular Probes Nucleic Acid Synthesis Inhibitors Pharmacology Protein Conformation Reverse Transcriptase Inhibitors Substrate Specificity Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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