Methylene bisphosphonates as the inhibitors of HIV RT phosphorolytic activity
| Autor: | Jouko Vepsäläinen, Dmitry V. Yanvarev, Marina K. Kukhanova, Elina Puljula, Sergey N. Kochetkov, N.N. Usanov, Olga A. Khomich, A. N. Korovina |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation DNA-Directed DNA Polymerase Biology urologic and male genital diseases Inhibitory postsynaptic potential Biochemistry 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Adenosine Triphosphate Magnesium Phosphorylation chemistry.chemical_classification Diphosphonates General Medicine Reverse transcriptase HIV Reverse Transcriptase 3. Good health 030104 developmental biology Enzyme chemistry Mutation HIV-1 Nucleic Acid Conformation RNA Viral Pharmacophore Thymidine Nucleoside Linker hormones hormone substitutes and hormone antagonists DNA |
| Zdroj: | Biochimie. 127 |
| ISSN: | 1638-6183 |
| Popis: | The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phosphorolytic activity of native and drug-resistant forms of HIV-1 reverse transcriptase (RT) was performed. It was shown that with the increase of the inhibitory potential of BPs towards the phosphorolytic activity raises their ability to inhibit the RT-catalyzed DNA elongation. Herein, we report the impact of the thymidine analog mutations (TAM) on the activity of bisphosphonates, as well as some structural features of the BPs, allowing them to maintain the inhibitory activity on the enzyme resistant to nucleoside analog therapy. We estimated the Mg2+-coordinating group structure, the linker and the aromatic pharmacophore influence on the inhibitory potential of the BPs. Based on the 31 BPs SAR, several BPs with improved inhibitory properties were designed and synthesized. |
| Databáze: | OpenAIRE |
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