Angela Corona1, Jenny Desantis2, Serena Massari2, Simona Distinto1, Takashi Masaoka3, Stefano Sabatini2, Francesca Esposito1, Giuseppe Manfroni2, Elias Maccioni1, Violetta Cecchetti2, Christophe Pannecouque4, Stuart F J Le Grice3, Enzo Tramontano5, Oriana Tabarrini6. 1. Dipartimento di Scienze della Vita e dell'Ambiente, Cittadella Universitaria di Monserrato, SS554, 09042, Monserrato, Italy. 2. Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy. 3. Basic Research Laboratory, National Cancer Institute, Frederick, MD, 21702-1201, USA. 4. Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research-KU Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium. 5. Dipartimento di Scienze della Vita e dell'Ambiente, Cittadella Universitaria di Monserrato, SS554, 09042, Monserrato, Italy. tramon@unica.it. 6. Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy. oriana.tabarrini@unipg.it.
Abstract
Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an appealing target. To identify new RNase H inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNase H activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNase H through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors.
Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in pan class="Species">HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an appealing target. To identify new RNase H inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNase H activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNase H through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors.
Authors: Mrinmoy Saha; Michael T Scerba; Nathaniel I Shank; Tracy L Hartman; Caitlin A Buchholz; Robert W Buckheit; Stewart R Durell; Daniel H Appella Journal: ChemMedChem Date: 2017-04-25 Impact factor: 3.466