EU: Application of Novel Cyclic Ligation Auxiliaries in the Study of Transthyretin and Derived Pathologies (CycLATTR)

The area of influence of proteins comprises 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 bio macromolecules 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 have 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, especially in Europe.

Principal investigators
Seitz, Oliver Prof. Dr. rer. nat. (Details) (Organic and Bioorganic Chemistry III)

Europäische Union (EU) - HU als Koordinator

Duration of project
Start date: 02/2013
End date: 01/2015

Last updated on 2022-08-09 at 21:09