权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular engineering of complementary glucose-responsive conformational switches in insulin and glucagon

胰岛素和胰高血糖素中互补葡萄糖响应构象开关的分子工程

基本信息

批准号：
10263301
负责人：
FARAMARZ ISMAIL-BEIGI
金额：
$ 58.36万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263301
关键词：
3-Dimensional Affinity Algorithms Animal Testing Animals Attenuated B-Lymphocytes Binding Biological Assay Biophysics Blood Blood Glucose Boron Boronic Acids Carbohydrates Cell Culture Techniques Cell physiology Chemistry Clinical Clinical Endocrinology Clinical Management Closure by clamp Complex Computer Simulation Computers Cryoelectron Microscopy Crystallization Data Dependence Development Devices Diabetes Mellitus Dose Elements Endocrinology Engineering Exclusion Female Formulation Foundations Glucagon Glucagon Receptor Glucose Glycols Goals Health Heteronuclear NMR Homeostasis Hormonal Hormone Receptor Hormone replacement therapy Hormones Hyperglycemia Hypoglycemia Injections Insulin Insulin Infusion Systems Insulin Receptor Insulin, Lispro, Human Insulin-Dependent Diabetes Mellitus Joints Lead Ligands Measures Metabolic Metabolism Methods Modeling Molecular Molecular Conformation Nature Non-Insulin-Dependent Diabetes Mellitus Outcome Patients Peptides Performance Pharmacology Physiology Play Positioning Attribute Property Protein Engineering Proto-Oncogene Proteins c-akt Publications Pump Rat-1 Rattus Receptor Signaling Recommendation Research Personnel Rest Risk Role Safety Scheme Series Somatostatin Specificity Stream Streptozocin Structure Synthesis Chemistry System Technology Time Variant Weight Gain Western Blotting X-Ray Crystallography Yang analog base clinical candidate design diabetic rat frontier hormone analog image reconstruction in silico in vivo innovation interdisciplinary approach male mathematical model multidisciplinary next generation novel operation particle patient subsets phosphoproteomics prototype simulation structural biology sugar three dimensional structure

项目摘要

Project Summary Insulin and glucagon play central roles in metabolic homeostasis with long-standing application to the clinical management of diabetes mellitus (DM). This MPI application focuses on the development of glucose-responsive analogs of these hormones. The proposed technology promises to enhance the safety and efficacy of hormone replacement therapy, including in innovative bihormonal pumps in closed-loop systems. This is a key frontier of molecular pharmacology and non-standard protein engineering. The multidisciplinary MPI team encompasses protein design, biophysics, structural biology, animal physiology, clinical endocrinology, and computer simulations of mammalian metabolism. Animal studies will be performed in normal and STZ rats under the guidance of Prof. F. Ismail-Beigi (Subcontract to CWRU); computer-based interpretation of these studies as part of a design cycle will be undertaken in simulated models by Prof. M. Strano and coworkers (Subcontract to MIT). Cryo-EM studies of variant insulin-insulin receptor (IR) complexes will be performed by Prof. M.C. Lawrence (Subcontract to WEHI, Melbourne AU). The MPI team has recent joint publications, including in Nature Chemistry, J. Biol. Chem. and Diabetes. Glucose-responsive insulin (GRI) analogs are envisioned as a technology to attenuate IR signaling under conditions of hypoglycemia; glucose-responsive glucagon (GRG) analogs are envisioned as a complementary technology to attenuate glucagon-receptor (GlR) signaling under conditions of hyperglycemia. Respective protein design rests upon two complementary premises: Hypothesis 1: That development of an appropriate glucose-binding element (GBE) will enable construction of a glucose-regulated conformational switch between a glucose-free closed (inactive) state and a glucose-bound open (active) state in accord with how WT insulin binds to and activates the IR; and Hypothesis 2: That development of a distinct GBE will enable construction of a glucose-regulated conformational switch between a glucose-bound inactive state and a glucose-free active state in accordance with how WT glucagon binds to and activates the GlR. In each case the GBEs will exploit the diol-binding properties boronic acids and benzoxaboroles. Binding of glucose in a GRI activates the hormone whereas binding of glucose in a GRG inactivates the hormone. Aims 1- 3 focus on GRIs whereas Aim 4 extends our approach to GRGs. These technologies may markedly enhance the long-term health of patients with T1D and a subset of patients with T2D. Protein design will be based on classical crystal structures of insulin and glucagon, extended by dramatic recent advances in the structural biology of the IR, GlR and their respective ligand complexes. Salient structural differences between these systems promise to enable construction of opposing switches. An interdisciplinary team Approach is proposed within integrated MPI Management Plan.

项目总结