Peptidomimetic drug design targeting G protein-coupled receptors

Currently available drugs in the market fall broadly into two categories. There are ‘small molecule' drugs (molecular weight of <500 Da) with oral bioavailability and much larger 'biologics' (molecular weight of typically >5000 Da) with no oral bioavailability. Due to their small size, small molecule drugs often suffer from reduced target specificity and toxicity. Large biologics, on the other hand, are highly target-specific and thus less toxic than small molecules. Therefore, the compounds that fit between these two molecular weights (500 Da-5000 Da) and possess the advantages of both the small molecule (e.g. bioavailability and stability) and larger biologics (e.g. highly target specific) are of great interest. Peptidomimetics are such compounds that fall into this category.

Relaxin family peptides have complex-two chain and three disulfide bonded structure and our laboratory has recently developed peptidomimetics of human relaxin 2 (B7-33), relaxin 3 (stapled peptide), and insulin-like peptide 5 (analogue 13). Projects are available to further develop these peptidomimetic ligands as molecular probes and drug leads that target their GPCR targets, relaxin family peptide (RXFP) receptors RXFP1, RXFP3 and RXFP4. These receptors are potential drug targets for cardiovascular disease, neurological disorders and gut dysfunction, respectively. Our laboratory utilizes multidisciplinary cutting-edge technologies including modern solid phase peptide synthesis, molecular pharmacology, and animal physiology to carry out these projects. Importantly, we are working with pharmaceutical industry partners (eg. Takeda and Novartis) to develop peptidomimetics therapeutically. Honours, Masters and PhD projects are available on multiple additional GPCR targets with training in various techniques as outlined above (also see projects from Prof Akhter Hossain).

Relevant Publications:

Pustovit R, Zhang X, Liew J, Praveen P, Liu M, Koo A, Oparija-Rogenmozere L, Ou Q, Kocan M, Nie S; Bathgate RAD, Furness J, Hossain, MA (2021) A Novel Antagonist Peptide Reveals a Physiological Role of Insulin-Like Peptide 5 in Control of Colorectal Function. ACS Pharmacology & Translational Science. 30;4(5):1665-1674

Praveen P, Tailhades J, Rosengren, KJ, Wade JD, Bathgate RAD*, Hossain MA* (2020) Effects of C-terminal B-chain modifications in a relaxin 3 agonist analog. ACS Medicinal Chemistry Letters 11: 2336-2340

Xiaozhou Z, Bathgate RAD*, Hossain MA* (2020) A13: B7-24 is the minimized two-chain structure of human INSL5. ACS Medicinal Chemistry Letters 11: 2455-2460

Lee H-S, Wang SH, Daniel JT, Hossain MA, Clark RJ, Bathgate RAD, Rosengren KJ (2020) Exploring the use of Helicogenic Amino Acids for Optimising Single Chain Relaxin-3 Peptide Agonists. Biomedicines 8, E415