Design, synthesis and evaluation of a novel inhibitor targeted at the NADPH site of nitric oxide synthase
| Autor: | Anny Slama-Schwok, Jean-Luc Boucher, Bogdan Tarus, Etienne Henry, Yun Li, Booma Ramassamy, Chantal Dessy, Eric Deprez, Hamid Dhimane |
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| Přispěvatelé: | Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Institut d'Alembert (IDA), Université Catholique de Louvain = Catholic University of Louvain (UCL) |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
biology Physiology Stereochemistry [SDV]Life Sciences [q-bio] Clinical Biochemistry Reductase Biochemistry Adenosine Nitric oxide synthase chemistry.chemical_compound Mediator chemistry Biosynthesis medicine biology.protein Moiety Phosphorylation Heme ComputingMilieux_MISCELLANEOUS medicine.drug |
| Zdroj: | Nitric Oxide 7. International Conference on the Biology, Chemistry and Therapeutic Application of Nitric Oxide 7. International Conference on the Biology, Chemistry and Therapeutic Application of Nitric Oxide, Jul 2012, Edinburgh, United Kingdom. ⟨10.1016/j.niox.2012.04.084⟩ |
| DOI: | 10.1016/j.niox.2012.04.084⟩ |
| Popis: | In mammals, NO is a signalling mediator that exerts a wide range of key physiological functions. The biological activities of NO are closely linked to the NO-synthase isoform involved in its synthesis and deregulation of its biosynthesis leads to several pathologies. Taking account of the crystallographic structures and of the critical role of the heme in catalysis, much effort has been dedicated to the design of inhibitors targeting the heme site. With the exception of diphenyliodonium and its close analogues, no chemical compound specifically targets the NADPH site of the reductase domain of NOS. In recent studies, we have characterized a NADPH analogue called nanotrigger NT1 that binds the NADPH site of the rductase domain of NOS. Following photoactivation, the terminal amine group of excited NT1∗ injected electrons to the FAD acceptor of NOS, thereby initiating the electron flow and catalysis. Based on molecular modelling studies, we designed and synthesized a novel prototype of NOS inhibitor, called nanoshutter (NS1) bearing a phosphorylated adenosine moiety as recognition motif of the NADPH site linked by an alkyl chain to a new chromophore. NS1 inhibited the formation of NO catalyzed by neuronal NOS in a dose-dependent manner. This inhibition was competitive and reversible with NADPH, in agreement with NS1 being addressed to the reductase domain of n NOS. Further work is in progress to improve the selectivity and affinity of this new class of NOS inhibitors and to explore the pharmacological properties of NS1. The photochemical properties of NS1 are also under investigation. |
| Databáze: | OpenAIRE |
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