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NOVEL PYRIMIDINE DERIVATIVES AS NONNUCLEOSIDE INHIBITORS OF HIV REPLICATION

NOVEL PYRIMIDINE DERIVATIVES AS NONNUCLEOSIDE INHIBITORS OF HIV REPLICATION. A.V. Ivanov , V.T. Valuev-Elliston, S.N. Kochetkov, C. Pannecouque, J. Balzarini, K.L. Seley-Radtke, M.S. Novikov. Highly active antiretroviral therapy (HAART). Epivir ( lamivudine ; 3TC)

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NOVEL PYRIMIDINE DERIVATIVES AS NONNUCLEOSIDE INHIBITORS OF HIV REPLICATION

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  1. NOVEL PYRIMIDINE DERIVATIVES AS NONNUCLEOSIDE INHIBITORS OF HIV REPLICATION A.V. Ivanov, V.T. Valuev-Elliston, S.N. Kochetkov, C. Pannecouque, J. Balzarini, K.L. Seley-Radtke, M.S. Novikov

  2. Highly active antiretroviral therapy (HAART) • Epivir (lamivudine; 3TC) • Emtriva (emtricitabine; FTC) • Retrovir (zidovudine; AZT) • Videx (didanosine; ddI) • Viread (tenofovir) • Zerit (stavudine; d4T) • Ziagen (abacavir) • Viramune (Nevirapine) • Sustiva (Efavirenz) • Intelence (Etravirine) Reverse transcriptase Selzentry ( maraviroc) CCR5 рreceptor Integrase Isentress (raltegravir) • Agenerase (amprenavir) • Crixivan (indinavir) • Invirase (saquinavir) • Kaletra (lopinavir/ritronavir) • Norvir (ritonavir) • Prezista (darunavir) • Reyataz (atazanavir) • Viracept Protease

  3. FDA-approved non-nucleoside inhibitors of the reverse transcriptase (NNRTI) Delavirdine (DLV) Efavirenz (EFV) Nevirapine (NVP) Etravirine (ETV) Rilprivirine (TMC278)

  4. NNRTI binding site A number of amino acid substitutions in NNRTI binding site lead to formation of drug resistant HIV strains. These substitutions include: L100I K103N V106A V179I Y181C Y188L G190A P225H M230L

  5. Goals of the project Synthesis of novel substituted pyrimidines and their evaluation as potential anti-HIV agents • Groups involved • Synthesis: Volgograd State Medical University (Volgograd, Russia) – • P.I. Dr. M. Novikov. • Investigation of antiretroviral activity in infected cell cultures: Rega Institute for Medical Research, K.U. Leuven (Leuven, Belgium) • P.I. Prof. J. Balzarini • Evaluation of the compounds as inhibitors of the wild-type and drug-resistant reverse transcriptases: Engelhardt Institute of Molecular Biology • P.I. Prof. S. Kochetkov

  6. 1-[2-(2-Benzylphenoxy)ethyl]pyrimidines (1-3) 1-[2-(2-benzoylphenoxy)ethyl]pyrimidines (4-7) 1-3 4-7

  7. Activity against mutant drug-resistant RTs 2 3

  8. Acknowledgements Prof. Christophe Pannecouque, Prof. Jan Balzarini Vladimir Valuev-Elliston Dr. Alexander Ivanov Prof. Sergey Kochetkov Prof. Katherine Seley-Radtke Dr. Mikhail Novikov

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