11:30 – 12:00
Dr Louise Walport: Structurally diverse cyclic peptides as potent inhibitors of the BET bromodomains
12:00 – 13:00
Main Visiting Speaker – Dr Andrew Jamieson: Rationally Designed Peptidomimetics: New Tools for Chemical Biology
Abstract
Peptides are well known to act as potent and selective ligands for a variety of bimolecular targets. Although there are many peptide drugs in clinical use, their potential has been limited by unfavorable physicochemical properties including limited plasma stability and a lack of cell permeability. Peptidomimetics are molecules that can be rationally designed to overcome many of the issues associated with peptides and provide tool molecules for chemical biology and lead compounds for drug discovery.
Disulfide bonds play an important structural and/or catalytic role in many peptides. However the synthesis of peptides containing more than one disulfide-bond is not trivial. Disulfide bond rich peptides and proteins are also susceptible to disulfide bond shuffling and reduction catalysed by glutathione. As such, an effective surrogate that accurately mimics a disulfide bond would be a powerful tool in chemical biology with a range of applications from understanding protein-folding mechanisms to peptide drug discovery.
In this seminar I will discuss my research groups work on developing a 1,5-disubstitiuted 1,2,3-triazole as a highly effective disulfide bond mimic. Application of this chemistry to disulfide bond rich conotoxin peptides will be presented together with structural characterisation using NMR. Biological assessment of these bioactive peptidomimetics against human muscle-type nicotinic acetylcholine receptors has also been determined. I will also present our most recent data on alpha-helical conotoxin peptidomimetics that target sodium ion-channels.
References
A. Knuhtsen, C. Whitmore, F. S. McWhinnie, L. McDougall, R. Whiting, B. O. Smith, C. M. Timperley, C. Green, K.I. Kinnear, A. G. Jamieson, Chem. Sci., 2019, Advance Article (doi:10.1039/C8SC04198A)
G. C. Clark, N. R. Casewell, C. T. Elliott, A. L. Harvey, A. G. Jamieson, P. N. Strong, and A. D. Turner, Trends Biochem Sci., 2019 (doi:10.1016/j.tibs.2018.12.004) (In Press)
Biography
Andrew Jamieson was born in Glasgow and raised in Strathaven, Scotland.
In 2003, he completed a BSc Honours degree (1st Class) in Chemistry with Medicinal Chemistry at the University of Glasgow. He subsequently studied for a Ph.D. at the University of Glasgow under the supervision of Dr Andrew Sutherland. The aim of his Ph.D. was to investigate a new substrate directed, palladium-catalysed aza-Claisen rearrangement, and utilise this novel reaction for the synthesis of natural products.
In 2007, he took up a postdoctoral research fellowship with Professor William Lubell at the University of Montreal, Canada. During this time he developed a novel synthetic method with which to systematically scan peptides for secondary structure. His research emphasis was determining the bioactive conformation of the growth hormone secretagogue, GHRP-6, as well as the allosteric modulator of the IL-1 receptor, 101.10 (rytvela).
In 2008, he took up a postdoctoral position with Professor Andrew Hamilton FRS at Yale University, USA. While there he worked on the design and synthesis of a novel peptide beta-strand mimetic, before moving with Professor Hamilton in 2009 to the University of Oxford, UK.
In August 2010, he was appointed to a lectureship in the Centre for Chemical Biology in the Department of Chemistry at the University of Leicester, UK. He was then appointed as a senior lecturer in Chemical Biology at the University of Glasgow School of Chemistry in July 2016. Andrew is currently the Chair of the Royal Society of Chemistry Chemical Biology and Bio-Organic Chemistry Group (CBBG).
Andrew and his wife, Sarah, have two children (James and Finlay). His main hobbies outside of chemical biology are running, rugby and snowboarding.