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).
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