Small molecule mimics of trans-proline: synthesis and applications

Abstract

Herein we detail the synthesis and application of small molecules of trans-proline mimics. A general introduction to the field of peptidomimetics and their uses in specific biological examples is provided; followed by a detailed review of the background and objectives of the project. The synthesis of trans-proline mimics using (–)-cytisine as a building block is disclosed. Its application is demonstrated by incorporation of (–)-cytisine derivatives in a specific anti-cancer peptide PRGPRP and determination of its anti-cancer activity. The synthesis and conformational analysis of a pyroglutamate based mimic, a trans-proline mimic designed to adopt a polyproline type II (PPII) helical conformation, is described. Incorporation of this mimic in the anti-cancer peptide PRGPRP and determination of its anti-cancer activity displays a useful application. To investigate the conformation of the pyroglutamic based mimic, synthesis and conformational analysis of its oligomers is detailed. Using circular dichroism (CD) spectroscopy, NMR and X-ray crystallographic structures, the PPII conformation of these oligomers are compared to the ideal PPII helices and known PPII mimics. A specific protein-ligand interaction (SH3-peptide ligand) is discussed. Incorporation of the pyroglutamic based mimic in the peptide sequence and its binding properties are disclosed. As a result of these studies, a second generation pyroglutamate based mimic is currently under development in the group to further investigate conformational analysis and binding properties with SH3.

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Identifiers

ORCID for Sally Bloodworth: orcid.org/0000-0003-2219-3635

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