Novel Glucose Responsive Insulin for Improved Treatment of Diabetes

新型葡萄糖反应胰岛素可改善糖尿病的治疗

基本信息

批准号：
10250801
负责人：
Pawel Fludzinski
金额：
$ 18.4万
依托单位：
AMIDEBIO, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250801
关键词：
Adult Affinity Amputation Binding Binding Sites Biological Assay Blindness Blood Glucose Calorimetry Caring Characteristics Clinical Trials Complications of Diabetes Mellitus Computing Methodologies Coupled Cryoelectron Microscopy Data Development Diabetes Mellitus Dialysis procedure Fructose Glucose Goals Human Hypoglycemia IGF1 gene Incidence Insulin Insulin Infusion Systems Insulin Receptor Insulin-Dependent Diabetes Mellitus Kidney Diseases Lead Legal patent Leucine Ligand Binding Ligands Maintenance Measures Methodology Methods Molecular Conformation Monitor Mutation Neuropathy Non-Insulin-Dependent Diabetes Mellitus Pancreas Patients Phase Physiological Process Production Property Proteins Quantitative Structure-Activity Relationship Rapid screening Retinal Diseases Screening procedure Series Somatomedins System Testing Thermodynamics Time Toxicology Trees Type 2 diabetic Valine Xylose analog base biophysical properties carbene cardiovascular risk factor clinical candidate computational platform computerized tools design diabetic drug candidate euglycemia global health glycemic control healthy volunteer improved in silico in vivo insight insulin Wakayama lead candidate lead series machine learning algorithm milligram novel pharmacokinetics and pharmacodynamics phase 2 study receptor receptor binding response screening small molecule standard of care success type I diabetic vigilance web server

项目摘要

SUMMARY/ABSTRACT. Diabetes is rapidly becoming a global health crisis. Depending on the type of statistical methodology used, the world-wide incidence of the most common type of diabetes, adult-onset or Type II, is estimated to be in the range of 285 million. In both Type I and Type II diabetics glycemic control is paramount as the inability to maintain glycemic control results in several secondary complications including neuropathy, nephropathy and retinopathy, that often lead to amputations, dialysis and blindness as well as increased risk of cardiovascular complications. For the majority of diabetics glycemic control requires constant vigilance and monitoring of blood glucose levels. The overarching goal of this project is the development of a novel glucose responsive insulin (GRI) with a reversible, glucose dependent response at the insulin receptor. The full realization of the GRI concept would most closely mimic the benefits of a healthy pancreas and maintain euglycemia, reduce/eliminate the need for constant monitoring, and ultimately, reduce/eliminate the complications of diabetes. The scope of this proposal is the design and testing of a series of analogs that can bind glucose allosterically and demonstrate differential response at the insulin receptor. This will be achieved through completion of three aims. In Aim 1 we will use a novel computational platform to design and produce a series of GRIs with glucose binding affinity in the physiological range. In Aim 2 we will determine the glucose binding affinity of the analogues produced in Aim 1. Finally, in Aim 3 we will measure the insulin receptor (IR) and insulin like growth factor (IGF-R1) affinity of the GRI’s in the presence of glucose at physiological concentrations. Completion of these Aims will result in the identification of several GRI lead candidates with glucose binding in the physiological range and reversible glucose dependent insulin receptor binding and absence of IGF-1R binding.

摘要/摘要。糖尿病正在迅速进行全球健康危机。据估计，最常见类型的糖尿病类型的糖尿病类型的事件估计在该范围内 I型和II型糖尿病患者的2.85亿血糖控制导致严重性次要的同情神经病，肾病和视网膜病，这通常会导致截肢，透析和失明，如心血管汇编。对于大多数糖尿病患者，糖尿病控制都需要对血糖水平的警惕和监测。该项目的总体目标是开发胰岛素受体的可逆，依赖性分辨率。最亲密地模仿健康胰腺尤利克血糖的好处，减少/消除了对最终监视，最终减少/消除糖尿病的汇编。是否设计和测试可以结合葡萄糖并证明差异的类似物的一系列类似物在胰岛素受体中的反应。新的计算平台，设计和生产一系列具有葡萄糖结合亲和力的GRIS AIM 2中的Physiololocal范围。最后，在AIM 3中，我们将测量胰岛素受体（IR）和胰岛素类似生长因子（IGF-R1）的亲和力 Gri在生理构想中存在葡萄糖的情况下。在生理范围内识别具有葡萄糖结合的几种GRI铅候选物葡萄糖依赖性胰岛素受体结合和IGF-1R结合的不存在。