Potential 2006 Honours Project

New drugs for diabetes: Peptidomimetic inhibitors of starch-degrading enzymes.

Delaying the absorption of dietary glucose has emerged as an effective approach to improving glycaemic control in non-insulin dependent diabetics. This can be achieved by diet (eg. Low GI foods) or by drug treatment with the α-glucosidase inhibitors acarbose, voglibose and miglitol. Salivary and pancreatic α-amylases are also attractive targets for delaying starch breakdown and several protein based selective amylase inhibitors are known. Tendamistat, a 71 residue protein from Streptomyces tendae 4158 was a promising candidate for management of type II diabetes, however it failed to progress due to observed antigenicity. Tendamistat contains a type I β-turn that presents a Trp-Arg-Tyr (WRY) motif which is fundamental to binding α-amylase. Modified small peptides that mimic WRY motif in the native structure with retention of affinity may be successful inhibitors without the antigenic properties. Cyclic peptides that can mimic the native conformation of tendamistat will be designed using computational modelling, and then synthesized using solid phase techniques. The conformational properties of the resultant peptides in solution will be analysed by 2D-NMR. Products will be analysed for inhibitory potency against pancreatic and salivary α-amylase using a high throughput colourimetric assay. This activity will be compared to other compounds, including the potent but non-selective inhibitor acarbose, to develop structure-activity relationships.

References:
Wiegand, G., Epp, O., Huber, R. J. Mol. Biol. 1995, 247, 99-110;

Supervisors: Dr Philip Thompson and Dr David Chalmers