Objective Phosphate ester hydrolysis is one of the most important classes of chemical reactions in biology, playing a central role in nucleic acid processing, energy transduction, and signalling. Despite the importance of this ubiquitous reaction, the mechanistic details of phosphate ester cleavage remain obscure due to the complex nature of the reaction. In addition, there is an active debate concerning possible reaction intermediates. Here we aim to clarify the molecular basis of this enzymatic mechanism by studying P-O bond cleavage by Nucleoside Triphosphate (NTP) - processing enzymes and by the HIV-RT system. Hydrolysis of NTP represents a biochemical reaction essential in most processes of life: energy storage and transfer, replication of the genetic material, translation, regulation, etc. We will clarify the roles of metal ions in NTP enzymes and the ubiquitous arginine finger-type interaction occurring during the catalytic process. Phosphate hydrolysis is also catalysed by the HIV-RT enzyme. HIV-RT is a main drug target for AIDS disease. Unfortunately, current HIV drugs cannot cure the disease, forcing patients to remain on viral suppressant medications indefinitely. The major emerging problem with the current HIV viral drugs is the acquired drug resistance. To combat this problem, it is essential to design new drugs that target alternative functions and binding sites. More than half of the current HIV drugs target the HIV-RT reverse transcriptase function. Nevertheless, HIV-RT also carries out an RNase H function that is essential to viral replication. Here, we aim to obtain detailed information on the conformational flexibility and tautomerism of the inhibitors and to find the link between these properties and the potency and selectivity of the RNase function inhibitors. By exploring the flexibility of the inhibitors as well as mutations in the protein, we also aim to identify how drug resistant mutants may emerge as a result of drug therapies. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acidsmedical and health scienceshealth sciencesinfectious diseasesRNA virusesHIVmedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancenatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural scienceschemical sciences Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2013-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Call for proposal FP7-PEOPLE-2013-IEF See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator KING'S COLLEGE LONDON EU contribution € 309 235,20 Address STRAND WC2R 2LS London United Kingdom See on map Region London Inner London — West Westminster Activity type Higher or Secondary Education Establishments Administrative Contact Paul Labbett (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
