Novel Design of a Fast-On/Fast-Off Insulin Analog for Closed-Loop Systems

描述（由申请人提供）：胰岛素输送的闭环系统-包括胰岛素泵、连续葡萄糖监测仪和基于反馈的控制算法-提供了一种有前途的技术，能够在1型糖尿病中实现严格的血糖控制，同时改善患者的便利性和依从性。这种耦合装置（也称为“人工胰腺”）的安全性和功效将通过开发新型胰岛素类似物制剂来增强，所述新型胰岛素类似物制剂将快速吸收与胰岛素信号传导的迅速“关闭”相耦合。尽管正在研究多种技术来加速吸收（基于药代动力学的方法; PK），但尚不清楚一旦在靶组织中形成了生产性激素-受体复合物，如何缩短胰岛素信号传导的内在细胞持续时间（基于药效学的方法; PD）。因为闭环系统中的一个关键挑战是从瞬时过度交付事件中恢复。理想的泵胰岛素将结合联合收割机快速PK和缩短PD。我们发明的双重PK-PD优化的胰岛素类似物制剂的灵感来自于最近对胰岛素如何与胰岛素受体（IR）结合的分子基础的结构见解。一个由学术研究人员组成的国际团队， 由M. A.凯斯西储大学医学院的韦斯已经定义了胰岛素如何与IR胞外域中的主要结合位点（指定为位点1）结合（在Nature（2013）中出版）。位点1与辅助位点2的生化探针偶联的阐明使得能够在1型糖尿病的啮齿动物模型（链脲佐菌素处理的Sprague-Dawley大鼠）中设计具有缩短的PD持续时间的新型胰岛素类似物。双位点1/位点2协同优化为胰岛素类似物设计提供了创新范例。我们的产品被指定为Tryptolog，因为必需元素是色氨酸取代亮氨酸位置A13（胰岛素背面邻接位点2的非保守残基）。我们推测，这个庞大的芳香族残基foreshortens分子之间的沟通，胰岛素触发的IR胞外域和其细胞内酪氨酸激酶结构域，反过来又增强了胰岛素信号。在本Phae 1 SBIR申请中，我们寻求以下支持：（i）通过位点1位点A8和B24的共修饰进一步优化和表征Tryptolog产品，以及（ii）在与人类患者比Sprague-Dawley大鼠更相关的猪模型中进行比较验证。猪研究将在Legacy Health Systems（波特兰，OR）由W. K.沃德是闭环系统专家，也是经验丰富的猪调查员。

DESCRIPTION (provided by applicant): Close-loop systems of insulin delivery-comprising an insulin pump, continuous glucose monitor, and feedback-based control algorithm-provide a promising technology to enable tight glycemic control in Type 1 diabetes mellitus with improved patient convenience and compliance. The safety and efficacy of such coupled devices (also known as an "artificial pancreas") would be enhanced by the development of novel insulin analog formulations that coupled rapid absorption with prompt "turn off" of insulin signaling. Whereas multiple technologies are under investigation to accelerate absorption (approaches based on pharmacokinetics; PK), it is not known how to foreshorten the intrinsic cellular duration of insulin signaling once a productive hormone- receptor complex has been formed in target tissues (approaches based on pharmacodynamics; PD). Because a key challenge in closed-loop systems is recovery from transient over-delivery events. An ideal pump insulin would combine rapid PK with foreshortened PD. Our invention of a dual PK-PD optimized insulin analog formulation was inspired by recent structural insights into the molecular basis of how insulin binds to the insulin receptor (IR). An international team of academic investigators, co-led by the laboratory of M. A. Weiss at Case Western Reserve University School of Medicine, has defined how insulin binds to its primary binding site (designated Site 1) in the IR ectodomain (in press in Nature (2013)). Elucidation of Site 1 coupled with biochemical probes of ancillary Site 2 enabled design of novel insulin analogs with abbreviated PD duration in a rodent model of Type 1 diabetes (streptozotocin- treated Sprague-Dawley rats). Dual Site 1/Site 2 co-optimization provides an innovative paradigm for insulin analog design. Our product is designated Tryptolog as an essential element is substitution of leucine position A13 (a non- conserved residue on the back surface of insulin adjoining Site 2) by tryptophan. We hypothesize that this bulkier aromatic residue foreshortens molecular communication between the hormone-triggered IR ectodomain and its intracellular tyrosine-kinase domains, in turn abbreviating the insulin signal. In this Phae 1 SBIR application we seek support for (i) the further optimization and characterization of Tryptolog products by co- modification of Site 1 sites A8 and B24 and (ii) their comparative validation in a pig model more relevant to human patients than Sprague-Dawley rats. Pig studies will be conducted at Legacy Health Systems (Portland, OR) by Dr. W. K. Ward, an expert on closed-loop systems and experienced pig investigator.