Optimizing diabetes therapy: re-engineering insulin as a biased agonist

 描述（由申请人提供）：胰岛素对1型糖尿病（DM）的治疗至关重要，并且通常需要用于2型DM的最佳管理。尽管其临床应用已有数十年，但胰岛素复杂的受体后信号传导特性包括治疗和非治疗作用。该I期SBIR应用的首要目标是证明原理证明，可以选择性地重新设计细胞水平上胰岛素的信号传导特性，以优化血糖控制，同时避免不良生物学作用。这种选择性的重新设计，一般指定的偏见激动，代表了一个关键的新兴前沿的分子药理学。诺贝尔奖获得者Michael Brown和Joseph Goldstein强调了选择性胰岛素抵抗在T2 DM中的重要性，其导致高胰岛素血症、高血糖症和高甘油三酯血症的经典三联征。他们指出：“随着脂肪酸和甘油三酯升高对糖尿病状态的不利影响的认识，肝脏中选择性胰岛素抵抗的概念变得越来越重要。”“2型糖尿病患者的暴力治疗 大剂量的野生型胰岛素可以克服胰岛素抵抗并控制血糖，但代价是什么？“（Brown，M.S.，和戈尔茨坦，J.L.选择性胰岛素抵抗与总胰岛素抵抗：一个致病悖论。细胞代谢7，95-6。（2008））。在该范例中，对胰岛素降糖作用的选择性抗性完整地保留了胰岛素在脂质合成和促有丝分裂性方面的不良信号传导特性。通过胰岛素受体的信号传导原则上可以导致偏向的信号传导结果，最近已经在噬菌体展示衍生的肽激动剂的动物研究中得到证实（Frikke-Schmidt，H.，佩德森，T.A.，Fledelius，C.，奥尔森，G.S.，Bouman，S. D.，Fitch，M.，& Hellerstein，M.用胰岛素或合成的胰岛素受体激动剂肽治疗糖尿病大鼠导致不同的代谢反应。Diabetes（E-pub Oct.14，2014））。本申请建立在最近对胰岛素受体胞外域中保守的胰岛素结合口袋的结构阐明的基础上，以设计具有偏向激动剂性质的非标准胰岛素类似物。初步研究表明，这种新的类似物保留了降糖活性，在人类癌细胞培养物中其促有丝分裂性显著减弱，并且在动物模型（Sprague-Dawley大鼠）中细胞信号传导转向肌肉中的糖原合成。需要提供支持，以便更全面地分析这些信号传导特性，并表征胰岛素类似物的结构和稳定性。

 DESCRIPTION (provided by applicant): Insulin is essential to the treatment of Type 1 diabetes mellitus (DM) and is often required for optimal management of Type 2 DM. Despite its many decades of clinical use, the complex post-receptor signaling properties of insulin include both therapeutic and non-therapeutic effects. The overarching objective of this Phase I SBIR application is to demonstrate proof-of-principle that the signaling properties of insulin at the cellular level may be selectively re-engineered to optimize glycemic control while avoiding undesirable biological actions. Such selective re-engineering, in general designated biased agonism, represents a key emerging frontier of molecular pharmacology. Nobel Laureates Michael Brown and Joseph Goldstein have highlighted the importance of selective insulin resistance in T2 DM leading to the classic triad of hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. "The concept of selective insulin resistance in the liver assumes increased importance with the realization that elevated fatty acids and triglycerides make detrimental contributions to the diabetic state," they note. "Brute-force treatment of type 2 diabetes patients with large doses of [wild-type] insulin... can overwhelm the insulin resistance and control the blood sugar, but at what price?" (Brown, M.S., & Goldstein, J.L. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7, 95-6. (2008)). In this paradigm selective resistance to the glucose-lowering effects of insulin leaves intact undesirable signaling properties of insulin with respect to lipid synthesis and mitogenicity. That signaling through the insulin receptor can in principle lead to biased signaling outcomes has recently been demonstrated in animal studies of a phage-display-derived peptide agonist (Frikke-Schmidt, H., Pedersen, T.A., Fledelius, C., Olsen, G.S., Bouman, S.D., Fitch, M., & Hellerstein, M. Treatment of diabetic rats with insulin or a synthetic insulin receptor agonist peptide leads to divergent metabolic responses. Diabetes (E-pub Oct. 14, 2014)). This application builds on the recent structural elucidation of a conserved hormone-binding pocket in the ectodomain of the insulin receptor to design a non-standard insulin analog with biased agonist properties. Preliminary studies suggest that this novel analog retains glucose-lowering activity with marked attenuation of its mitogenicity in human cancer cell culture and that in an animal model (Sprague-Dawley rats) cellular signaling is shifted toward glycogen synthesis in muscle. Support is requested to enable a more complete analysis of these signaling properties and to characterize the structure and stability of the insulin analog.