Obiettivo The area of influence of proteins comprise most biochemical reactions and recognition process that govern a living body. However, its malfunction often lead to devastating diseases, like the ones related to Transthyretin:famylial amyloid polyneuropathy (FAP), famylial amyloid cardiomyopathy (FAC) and systemic senyl amyloidosis (SSA), cureless to date. Chemical approaches to some of these biomacromolecules have been possible after the discovery of the native chemical ligation, which involves assembly of unprotected Cys-peptide and peptidyl-thioester fragments in aqueous environments. Nonetheless, this technique still encompasses major limitations that has prevented its application to virtually all proteins, such as the requirement of N-terminal Cys peptides and low yield in bulky ligation sites. To increase the scope of ligation, thiol-containing building blocks and thiol-directing ligation auxiliaries have been designed, which allow ligation at non-cysteine ligation sites, but are either sequence dependent or lack sufficient efficiency.In this proposal, we aim to introduce new families of ligation auxiliaries that overcome the classical restrictions of this technique and improve previous strategies. In more detail, two complementary templates will be investigated: mercapto-cyclopentadienil and mercapto-cyclopropylethyl. The former structure is specifically designed to enhance the ligation rate by placing the thiol group in an ideal position with respect to the nitrogen, whereas the latter decreases the sterical hindrance and enhances the acid lability of the auxiliary. To practically illustrate the applicability of this new methodology, the native sequence and mutated analogues of Transthyretin at critical positions will be chemically achieved, a major milestone in the study of this protein, thereby helping understand the biochemical mechanisms that produce the derived pathologies, which cause the death of several thousand people in the world, specially in Europe. Campo scientifico natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicinepathology Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2011-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Invito a presentare proposte FP7-PEOPLE-2011-IEF Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IEF - Intra-European Fellowships (IEF) Coordinatore HUMBOLDT-UNIVERSITAET ZU BERLIN Contributo UE € 167 390,40 Indirizzo UNTER DEN LINDEN 6 10117 Berlin Germania Mostra sulla mappa Regione Berlin Berlin Berlin Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Renate Ubachs (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
