TAILIEUCHUNG - Báo cáo khoa học: Alizarine derivatives as new dual inhibitors of the HIV-1 reverse transcriptase-associated DNA polymerase and RNase H activities effective also on the RNase H activity of non-nucleoside resistant reverse transcriptases

HIV-1 reverse transcriptase (RT) has two associated activities, DNA poly-merase and RNase H, both essential for viral replication and validated drug targets. Although all RT inhibitors approved for therapy target DNA poly-merase activity, the search for new RT inhibitors that target the RNase H function and are possibly active on RTs resistant to the known non-nucleoside inhibitors (NNRTI) is a viable approach for anti-HIV drug development. | IFEBS Journal Alizarine derivatives as new dual inhibitors of the HIV-1 reverse transcriptase-associated DNA polymerase and RNase H activities effective also on the RNase H activity of non-nucleoside resistant reverse transcriptases Francesca Esposito1 Tatyana Kharlamova1 Simona Distinto2 Luca Zinzula1 Yung-Chi Cheng3 Ginger Dutschman3 Giovanni Floris1 Patrick Markt4 Angela Corona1 and Enzo Tramontano1 1 Department of Applied Sciences in Biosystems University of Cagliari Italy 2 Department of PharmacobiologicalSciences University of Catanzaro Italy 3 Deprtment of Pharmacology Yale University Medical School New Haven CT USA 4 Department of PharmaceuticalChemistry University of Innsbruck Austria Keywords anthraquinones HIV-1 ribonuclease H NNRTI-resistant RNase H RT inhibitors Correspondence E. Tramontano Department of Applied Sciences in Biosystems University of Cagliari Cittadella di Monserrato SS554 09042 Monserrato Cagliari Italy Fax 39 070 675 4536 Tel 39 070 675 4538 E-mail tramon@ Received 30 December 2010 revised 7 February 2011 accepted 21 February 2011 doi HIV-1 reverse transcriptase RT has two associated activities DNA polymerase and RNase H both essential for viral replication and validated drug targets. Although all RT inhibitors approved for therapy target DNA polymerase activity the search for new RT inhibitors that target the RNase H function and are possibly active on RTs resistant to the known nonnucleoside inhibitors NNRTI is a viable approach for anti-HIV drug development. In this study several alizarine derivatives were synthesized and tested for both HIV-1 RT-associated activities. Alizarine analogues K-49 and KNA-53 showed IC50 values for both RT-associated functions of 10 IM. When tested on the K103N RT both derivatives inhibited the RT-associated functions equally whereas when tested on the Y181C RT KNA-53 inhibited the RNase H function and was inactive on the polymerase function. Mechanism of action .

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