Peptides derived from natural sources are useful lead compounds to develop therapeutics. The structural diversity of naturally occurring peptides covers a large section of chemical space that sits between more traditional small molecules (<500 daltons) and biologics (typically proteins). Peptides typically have excellent selectivity and binding affinity for their targets. However, they have physicochemical issues that limit their development as drugs. These include poor blood plasma stability due to proteolytic degradation and limited bioavailability because they are unable to cross membrane structures, due to their inherent polarity. The Jamieson Group’s ongoing research program (Chem. Sci., 2019, 10, 1671) is focused on the development of new peptidomimetic chemistries that can be used to overcome the physicochemical limitations of peptides and facilitate peptide drug discovery. This is achieved by chemically modifying the peptide structure; removing the vulnerable functionality and introducing chemical mimic structures to retain the overall 3-dimensional structure of the peptide. Using these synthetic molecules we are investigating the nature of molecular recognition between conotoxins and the nicotinic acetylcholine receptor (nAChR).
Hypothesis: The central hypothesis of this project is to investigate whether synthetic mimics can be used to replace the disulfide bonds and complex disulfide bond networks found in conotoxin peptides and produce more stable analogues that retain the activity of the native peptides and can be used to probe the nature of molecular recognition with the nAChR.
i) Advanced automated, microwave assisted solid phase synthesis of conotoxin peptides and peptidomimetics.
ii) Recombinantly express and purify acetylcholine binding protein (AChBP) and nAChR.
ii) Utilise structural biology techniques, including X-ray crystallography and cryo-EM, to solve the 3D structure of the AChBP and then acetylcholine receptor in complex with conotoxin peptide/peptidomimetics.
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