The Highly Active Antiretroviral Therapy (HAART) [1] consists of the combination of two or more drugs acting against three viral enzymes: reverse transcriptase, protease, and integrase (IN). The latter catalyzes integration of viral DNA with host DNA and was recently identified as a target for a promising class of drugs, Integrase Strand Transfer Inhibitors (INSTI).[2] Currently, three drugs that seem to inhibit efficiently IN-HIV-1, namely Raltegravir, Elvitegravir and Dolutegravir, have been approved by FDA (American Food and Drug Administration) for therapeutic use.[3] Nevertheless, the outbreak of drug resistance during the therapeutic approach requires continuous and unceasing design of new antivirals. Presently, our research efforts are focused on the development of new INSTI cytosine-based systems (as depicted in the figure) that originate from preliminary conformational analysis showing the core moiety to provide adequate facial orientation in the bioactive conformation, when functional groups suitable for insertion of additional structural elements are present in their molecules. Under our conditions, a first generation of molecules have already been prepared and also tested to assess their biological activity in vitro, at Xpress Bio-laboratories (Maryland (USA). Molecular docking analysis prompted the possibility to improve their potential inhibitory activity by structural modifications at the side chains and, therefore, we report herein the exploitation of our procedure to get a second generation of cytosine-based molecules that are presently under biological evaluation

Pursuing the Development of New Antiviral INSTIs

PEDATELLA, SILVANA;OSTACOLO, CARMINE;GOMEZ MONTERREY, ISABEL MARIA;
2015

Abstract

The Highly Active Antiretroviral Therapy (HAART) [1] consists of the combination of two or more drugs acting against three viral enzymes: reverse transcriptase, protease, and integrase (IN). The latter catalyzes integration of viral DNA with host DNA and was recently identified as a target for a promising class of drugs, Integrase Strand Transfer Inhibitors (INSTI).[2] Currently, three drugs that seem to inhibit efficiently IN-HIV-1, namely Raltegravir, Elvitegravir and Dolutegravir, have been approved by FDA (American Food and Drug Administration) for therapeutic use.[3] Nevertheless, the outbreak of drug resistance during the therapeutic approach requires continuous and unceasing design of new antivirals. Presently, our research efforts are focused on the development of new INSTI cytosine-based systems (as depicted in the figure) that originate from preliminary conformational analysis showing the core moiety to provide adequate facial orientation in the bioactive conformation, when functional groups suitable for insertion of additional structural elements are present in their molecules. Under our conditions, a first generation of molecules have already been prepared and also tested to assess their biological activity in vitro, at Xpress Bio-laboratories (Maryland (USA). Molecular docking analysis prompted the possibility to improve their potential inhibitory activity by structural modifications at the side chains and, therefore, we report herein the exploitation of our procedure to get a second generation of cytosine-based molecules that are presently under biological evaluation
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/611351
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