Quick Project Snapshot
Developing novel chemical methods to produce insulin mimetics
Central to the successful clinical use of new and improved insulin analogues is the availability of efficient methods to prepare them in high overall yield and purity. Previous chemical methods reported in the literature for stepwise disulfide bond formation for insulin assembly require special conditions such as harsh chemical reagents or enzymes that can modify some sensitive amino acid residues leading to lower yields. We have developed a novel procedure, where one of the three disulfide connections in insulin is formed in aqueous media by irradiation with light resulting in significantly improved overall yield. However, this method can further be improved. Our team will focus on advancing current photochemistry knowledge to develop new ways of making two or all three disulfide bonds in insulin under ambient conditions. We will use this improved method for developing novel insulin analogues with better pharmacokinetic properties. Native human insulin, for example, suffers from a short survival time in blood. Longer acting insulin analogues (such as Lantus and Levemir) have recently become available, but they have side effects. Lantus, for example, causes a pathological condition called “injection amyloidosis”. Therefore, development of longer acting but soluble and non-amyloidogenic form of insulin is highly desirable. Our team aims to efficiently synthesize soluble, non-fibrilogenic and more stable insulin analogues for future clinical evaluation. More specifically, chemical synthesis of insulin and analogues will be achieved by using wavelength-selective orthogonality. We will engineer non-fibrilogenic insulin analogues by site-specific glycosylation to slow down liver-mediated decomposition. Pre-clinical evaluation of insulin analogues will be tested both in vitro (cell based assay) and in vivo (animal models).
Insulin Peptides Group
Insulin is one of the most clinically important peptide drugs on the market. It still represents the only treatment for diabetes (particularly for type 1). There are seven other insulin-like peptides (also called the relaxin family of peptides: H1, H2 and H3 relaxins, INSL3, 4, 5 and 6) which have similar structures to insulin (2 chains, 3 disulfide bonds), but have a diverse range of physiological functions. H2 relaxin is the most studied peptide in our laboratory and has recently passed phase III clinical trials for the treatment of acute heart failure. Our interest and experience lies in the design and development of insulin and insulin-like peptide-based drugs.
All Projects by this LabDeveloping peptidomimetics of insulin-like peptide 5, a novel orexigenic gut hormone, to target its GPCR, RXFP4Developing novel chemical methods to produce insulin mimeticsDeveloping small peptidomimetics to target RXFP1 for the treatment of acute heart failureNovel single-chain peptide mimetics, B7-33, for the treatment of fibrosisNovel relaxin-3 mimetics for controlling feeding and motivated behaviourNovel insulin-like peptide 5 mimetics for controlling colon motilityNovel insulin mimetics for managing diabetes
The Neuropeptides Division primarily conducts multi-disciplinary studies on the relaxin family of peptides/hormones and their receptors. The division focuses on determining the role of these peptides and the receptors they target a wide range of physiological and disease states. These studies are coupled with fundamental drug discovery research on both these and other peptides and their G protein-coupled receptors. The aim of this research is to develop new biological knowledge and fundamental understanding about how to best therapeutically target these peptide systems with the long term view to develop drugs which target the peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.
An example of the success of this approach is the completion of a Phase III trial using the hormone relaxin for the treatment of acute heart failure by the Swiss Pharmaceutical Company Novartis. A Phase IIIb trial is ongoing and the relaxin drug, serelaxin, has been approved in Russia to treat patients with acute heart failure. Hence fundamental research on the mechanism of action of a hormone, in the case of relaxin pioneered at the Florey by the former Neuropeptides Division Head, Prof Geoffrey Tregear, can ultimately lead to its use to treat disease in patients.