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

• 批准号: 10443890
• 负责人: FARAMARZ ISMAIL-BEIGI
• 金额: $ 49.03万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443890
• 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

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

项目成果

In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins.

• DOI: 10.1021/acsptsci.3c00095
• 发表时间: 2023-09
• 期刊: ACS pharmacology & translational science
• 影响因子: 6
• 作者: J. Yang;Sungyun Yang;Xun Gong;N. Bakh;Ge Zhang;Allison B. Wang;A. Cherrington;Michael A. Weiss;Michael S. Strano