Biological and Medicinal Chemistry Approaches to Human Beta Cell Regeneration

人类 β 细胞再生的生物和药物化学方法

基本信息

批准号：
10580818
负责人：
Robert J DeVita
金额：
$ 62.99万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2020-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10580818
关键词：
Adult Adverse effects Affect Agonist Antibodies Automobile Driving Beta Cell Biochemistry Bromodeoxyuridine Cell Count Cell Differentiation process Cell Proliferation Cell surface Cells Chemicals Complement Coupling Data Development Diabetes Mellitus Drug Combinations Engraftment Family Focus Groups Future GCG gene Goals Hand Harmine Human In Vitro Individual Insulin Insulin-Dependent Diabetes Mellitus Label Lead Metabolic syndrome Modeling Monoclonal Antibodies NOD/SCID mouse National Institute of Diabetes and Digestive and Kidney Diseases Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Outcome Parents Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Physiological Population Prediabetes syndrome Process Proliferating Proliferation Marker Reproducibility Research Personnel Residual state Risk Safety Series Specificity Structure of beta Cell of islet System Therapeutic Transforming Growth Factor beta United States National Institutes of Health Withholding Treatment Work analog antibody conjugate antibody inhibitor cell regeneration chemical synthesis cost effective delivery vehicle diabetic euglycemia exenatide feasibility testing improved in vivo in vivo regeneration indexing inhibitor insight islet novel optimism prototype receptor regenerative regenerative cell regenerative therapy small molecule targeted delivery type I and type II diabetes

项目摘要

Both Type 1 and Type 2 diabetes (T1D and T2D) result from inadequate numbers of normally functioning beta cells. Small molecule drugs that inhibit the kinase, DYRK1A, such as harmine and others, are reproducibly able to induce adult human beta cells to replicate, but at low rates (~2%/day). More recently, we have shown that adding any small molecule DYRK1A inhibitor to either a TGF-beta superfamily inhibitor (TGFβI's) or to a GLP1 receptor agonist such as GLP1 or exendin-4 markedly enhances this replicative induction to rates averaging 5-8%/day. This has been documented not only by “markers” of replication such as Ki67 and BrdU, both in vitro and in vivo, but also by enhancing actual numbers of beta cells. Unfortunately, these drugs may not exclusively affect the beta cell, but instead may have “off target” effects as well. Thus, diabetes researchers have effective regenerative drugs to deliver to the human beta cell, but may require a “targeting molecule” to bring them to the beta cell. Accordingly, over the past few years, diabetes researchers have identified two classes of “prototype beta cell targeting molecules”: a monoclonal antibody raised against the beta cell surface molecule called “ENTPD3”; and, the GLP1-receptor class of molecules. While these molecules may or may not be perfect for beta cell targeting, they are unquestionably “prototype” targeting molecules with which to work while the field attempts to identify more perfect beta cell targeting molecules. We have also synthesized numerous DYRK1A inhibitors and TGFbeta inhibitors and cleavable chemical linkers that enable their conjugation to any potential beta cell targeting molecule. Thus, the Aims of this application are: 1. Synthesis of TGF-beta Inhibitors With Chemical Linkers, to Complement our Novel DYRK1A inhibitor Linker Compounds, For Conjugation To Prototype Targeted Delivery Vehicles. 2. Conjugation of Harmine-Linker and TGF-beta-Inhibitor-Linker Compounds to Two Prototype Targeting Molecules: GLP1 Receptor Agonists and ENTPD3 Monoclonal Antibodies. 3. Definition of Long Term Efficacy, Specificity and Safety of the Harmine-Linker and TGF-beta Inhibitor- Linker Conjugates in vivo in Human Islet Engraftment Models. These goals are both achievable and directly responsive to the goals of aims of the NIDDK. If GLP1 receptor agonists and/or ENTPD3 MAbs prove suboptimal for beta cell targeting, the approaches and molecules developed here can readily be extended and adapted to any future more specific human beta cell targeting molecule.

1 型和 2 型糖尿病（T1D 和 T2D）都是由正常功能的 β 细胞数量不足引起的。抑制激酶 DYRK1A 的小分子药物（例如去氢骆驼蓬碱等）能够重复性地诱导成人 β 细胞复制。但以较低的速率（约 2%/天），最近我们已经证明，将任何小分子 DYRK1A 抑制剂添加到 TGF-β 超家族抑制剂 (TGFβI) 或中。 GLP1 受体激动剂（例如 GLP1 或 exendin-4）可显着增强这种复制诱导率，平均每天 5-8%，这不仅通过复制“标记”（例如 Ki67 和 BrdU）在体外和体内得到证明。不幸的是，这些药物可能不仅影响β细胞，而且还可能产生“脱靶”效应，因此，糖尿病研究人员拥有有效的再生药物来传递给人类β细胞。细胞，但可能需要“靶向分子”才能将它们带到β细胞因此，在过去几年中，糖尿病研究人员已经确定了两类“原型β细胞靶向分子”：针对β细胞表面产生的单克隆抗体。称为“ENTPD3”的分子；以及 GLP1 受体类分子，虽然这些分子可能适合也可能不适合 β 细胞靶向，但它们无疑是可用于该领域的“原型”靶向分子。我们还合成了许多 DYRK1A 抑制剂和 TGFβ 抑制剂以及可裂解的化学接头，使其能够与任何潜在的 β 细胞靶向分子缀合。因此，本申请的目的是： 1. 合成 TGF-β 抑制剂。化学接头，补充我们的新型 DYRK1A 抑制剂接头化合物，用于缀合至原型靶向递送载体。 2. Harmine-Linker 和 TGF-β-Inhibitor-Linker 化合物与两种原型靶向分子的缀合：GLP1 受体激动剂和 ENTPD3 单克隆抗体 3. Harmine-Linker 和 TGF-beta 的长期功效、特异性和安全性的定义。抑制剂-连接子在人胰岛移植模型中体内缀合。如果 GLP1 受体激动剂和/或 ENTPD3 MAb 被证明对于 β 细胞靶向效果不佳，那么这里开发的方法和分子可以很容易地扩展和适应任何未来更具体的人类。 β细胞靶向分子。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure-Function Analysis of p57KIP2 in the Human Pancreatic Beta Cell Reveals a Bipartite Nuclear Localization Signal.

人胰腺 β 细胞中 p57KIP2 的结构功能分析揭示了二分核定位信号。

DOI：
发表时间：
2023-12-23
期刊：
影响因子：
4.8
作者：
Choleva, Lauryn;Wang, Peng;Liu, Hongtao;Wood, Olivia;Lambertini, Luca;Scott, Donald K;Karakose, Esra;Stewart, Andrew F
通讯作者：
Stewart, Andrew F