Optimized Receptor Binding Profile in an Ultra-Stable, Ultra-Rapid-Acting Insulin

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DESCRIPTION (provided by applicant): We seek to develop an ultra-fast, zinc-free insulin analog formulation for the treatment of diabetes mellitus. An ultra-fast pharmacokinetic-dynamic (PK/PD) profile promises to enable superior performance of pump therapy (continuous subcutaneous insulin infusion) with enhanced safety and more robust integration with glucose- sensing technologies. Ultra-fast kinetics would also facilitate post-prandial glycemic control following single mealtime injections. The barrier to subcutaneous absorption is insulin self-assembly. The key component of an ultra-fast formulation would, thus, be an engineered insulin monomer with sufficient intrinsic chemical and physical stability to render zinc-mediated self-assembly unnecessary. Such an analog was developed 20 years ago (AspB10-insulin), but failed preclinical testing due to its potential tumorigenicity and increased in vitro mitogenicity relative to native insulin. These properties are thought to reflect increased binding to the IGF-I receptor (IGF-1R) and prolonged residence time at the insulin receptor (IR). We have discovered that a strategic fluoro-modification of an AspB10-insulin analog (a) eliminates undesirable binding to IGF-1R and prolonged IR residence time and, at the same time, (b) enhances the stabilizing effects of AspB10. The fluoro-modified residue is ortho-F-PheB24, which is amenable to insertion by chemical synthesis or by novel genetic engineering. Phase-I support is, therefore, requested to achieve milestones related to the stability, potency, mitogenicity, and PK/PD of fluoro-protected AspB10 analogs containing rapid-acting B-chain substitutions at positions B28 and B29 (derived from current products Humalog(R) and Novolog(R)). This proposal makes innovative use of fluorine (a mainstay of medicinal chemistry) in protein biotechnology to enhance the safety and efficacy of insulin replacement therapy. PUBLIC HEALTH RELEVANCE: Diabetes is increasing in global prevalence. To provide greater convenience, improved glycemic control, and fewer adverse side-effects (all of which result in greater compliance and lower healthcare costs), we have invented novel ultra-stable and ultra-rapid-acting insulin analogs (designated Fluorolog-1 and Fluorolog-2) that exhibit optimized receptor binding profiles attenuating unwanted effects of AspB10 on binding to the insulin receptor (IR) and the IGF-I receptor (IGF-1R), in principle reducing cancer risk. The innovative design of these analogs exploits fluorine-based electrostatic engineering to "tune" the stability, mitogenicity, and potency of an engineered Zn-free insulin monomer. This project will complete feasibility testing on Fluorolog-1 and Fluorolog-2.