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)的治疗是必不可少的，通常也是2型DM最佳治疗所必需的。尽管胰岛素的临床应用已有几十年，但其复杂的受体后信号传递特性包括治疗和非治疗作用。这一第一阶段SBIR应用的首要目标是证明原理证明，胰岛素在细胞水平的信号特性可以被选择性地重新设计，以优化血糖控制，同时避免不良的生物作用。这种选择性的再工程，通常被称为有偏见的激动剂，代表了分子药理学的一个关键的新兴前沿。诺贝尔奖获得者迈克尔·布朗和约瑟夫·戈尔茨坦强调了选择性胰岛素抵抗在T2 DM患者中的重要性，这会导致典型的高胰岛素血症、高血糖和高甘油三酯血症。他们指出，随着人们意识到脂肪酸和甘油三酯的升高对糖尿病状态的不利影响，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 使用大剂量的[野生型]胰岛素。可以压倒胰岛素抵抗，控制血糖，但代价是什么呢？(Brown，M.S.，&Goldstein，J.L.选择性与总胰岛素抵抗：一个致病悖论。梅塔布细胞。7，95-6。(2008))。在这个范例中，对胰岛素降糖作用的选择性抵抗使胰岛素在脂质合成和有丝分裂方面的不良信号特性保持不变。最近对噬菌体展示衍生的多肽激动剂(Frikke-Schmidt，H.，Pedersen，T.A.，Fledelius，C.，Olsen，G.S.，Bouman，S.D.，Fitch，M.和Hellerstein，M.)进行的动物研究证明，通过胰岛素受体传递的信号原则上可以导致有偏见的信号结果。糖尿病(E-pub，2014年10月14日)。这一应用建立在最近对胰岛素受体胞外区保守的激素结合口袋的结构阐明的基础上，以设计具有偏向激动剂特性的非标准胰岛素类似物。初步研究表明，这种新的类似物在人类癌细胞培养中保留了降糖活性，但其有丝分裂活性明显减弱，在动物模型(Spraogue-Dawley大鼠)中，细胞信号转移到肌肉中的糖原合成。需要支持以实现对这些信号特性的更完整的分析，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.