Halogenated Insulin: a fast-acting, ultra stable analog.

描述（由申请方提供）：拟定了一项临床前开发的I期SBIR项目，重点关注用于治疗糖尿病的新型速效胰岛素类似物。我们的产品被命名为Insulin-Cl，是赖脯胰岛素（HumalogTM的活性成分）的衍生物，在B链（PheB 24）中保守苯丙氨酸的芳环内含有一个氯取代。Insulin-Cl保留了残基B28和B29的互换（取代ProB28.Lys和LysB29.Pro），这使HumalogTM在皮下注射后快速吸收。胰岛素-Cl为患者提供了以下潜在优势：（i）更长的保质期和在高于室温的温度下降解的稳定性;以及（ii）可能作为无锌溶液配制以提供超快速吸收。目前的餐时胰岛素类似物如HumalogTM和NovalogTM比人胰岛素稳定性差，必须配制成锌胰岛素六聚体;因此，原则上吸收不如无锌制剂那么快。胰岛素-Cl的超快速吸收可以为患者提供更多的便利性，并且还可以增强与葡萄糖传感器耦合的闭环“智能泵”的安全性。我们试图测试胰岛素-Cl的候选制剂，并评估其在动物模型中的体内效力和药代动力学。Insulin-Cl是在凯斯西储大学发明的，目前正在Thermalin Diabetes，Inc.的许可下开发。主要研究者是赖脯胰岛素的共同发明人，他在胰岛素制剂的药学研究方面拥有40年的经验。 公共卫生相关性：糖尿病是一种在发达国家和发展中国家日益流行的疾病;患者寻求更大的便利性，改善血糖控制和更少的不良副作用，所有这些都导致更高的依从性和更低的医疗保健成本。该项目将完成Insulin-Cl的临床前开发，Insulin-Cl是一种潜在的超稳定和超速效胰岛素类似物，可方便地储存而无需冷藏，并可在接近进餐时间时服用，可减少餐后葡萄糖缺乏症。

DESCRIPTION (provided by applicant): A Phase 1 SBIR program of pre-clinical development is proposed focusing on a novel rapid-acting insulin analog for the treatment of diabetes mellitus. Designated Insulin-Cl, our product is a derivative of insulin lispro (the active component of HumalogTM) containing a single chloro-substitution within the aromatic ring of a conserved phenylalanine in the B-chain (PheB24). Insulin-Cl retains the interchange of residues B28 and B29 (substitutions ProB28 .Lys and LysB29.Pro) that confers upon HumalogTM its rapid absorption following subcutaneous injection. Insulin-Cl offers to patients the potential advantages of (i) greater shelf life and stability to degradation at temperatures above room temperature; and (ii) possible formulation as a zinc-free solution to provide ultra- rapid absorption. Current meal-time insulin analogs such as HumalogTM and NovalogTM are less stable than human insulin and must be formulated as zinc insulin hexamers; as a consequence, absorption is in principle not as rapid as could be provided by a zinc-free formulation. Ultra-rapid absorption of Insulin-Cl may offer added patient convenience and also enhanced safety in closed-loop "smart pumps" coupled to glucose sensors. We seek to test candidate formulations of Insulin-Cl and to assess its in vivo potency and pharmacokinetics in animal models. Insulin-Cl was invented at Case Western Reserve University and is being developed under license to Thermalin Diabetes, Inc. The principal investigator, who brings to this application four decades of experience in pharmacetical studies of insulin formulations, was co-inventor of insulin lispro. PUBLIC HEALTH RELEVANCE: Diabetes is an increasingly prevalent disease in the developed and developing worlds; patients seek greater convenience, improved glycemic control, and fewer adverse side-effects, all of which result in greater compliance and lower healthcare costs. This project will complete pre- clinical development of Insulin-Cl, a potentially ultra-stable and ultra-rapid acting insulin analog which could conveniently be stored without refrigeration and taken closer to meal time and could cause less post-meal glucose deficiency.