Development of DT-109 as an oral therapeutic for type 2 diabetes

 描述（由申请人提供）：2型糖尿病（T2 D）是一种以高血糖为特征的慢性疾病，并迅速成为一个全球性的卫生保健问题，到2030年可能达到大流行水平。目前，全世界有近3.5亿人患有糖尿病。糖尿病是心脏病和中风的主要原因，也会导致其他并发症，如视力丧失、肾衰竭和截肢或截肢。治疗T2 D的有效药物，如胰岛素和胰高血糖素样肽1（GLP- 1），需要注射，这是不方便和昂贵的。因此，开发更安全、更有效、更方便的口服药物对预防糖尿病流行是必要的。该SBIR的产品是DT-109的口服剂型，用于治疗T2 D。DT-109是一种三肽，口服给药时可通过增加GLP-1和胰岛素水平有效降低几种T2 D小鼠模型的血糖。由于DT-109由天然存在的L-氨基酸组成，因此它被认为是T2 D患者更安全，更便宜和方便的药物干预。该SBIR的长期目标是完成临床前开发，并确定合作伙伴或投资者联盟，以资助DT-109作为T2 D口服治疗药物的临床试验。Diapin Therapeutics已经证明DT-109通过G蛋白偶联受体（GPCR）起作用以引发其活性，并且GPCR文库的高通量筛选显示在160个GPCR中有3个命中作为激动剂。该I期假设是3种GPCR中的至少一种对于DT-109引发其活性是必需的。第一阶段SBIR提案有两个具体目标。目的1是确认高通量筛选的结果，并使用功能获得模型鉴定效应所需的特异性GPCR。目的2是使用功能丧失模型确定气相色谱还原的功能重要性。DT-109的MOA表征对于我们理解DT-109的药理学至关重要。本SBIR的II期将进行药代动力学/毒代动力学研究，并完成DT-109开放IND的数据集。DT-109口服剂型的专利已经发布，DT-109靶点的确定将有助于我们与大型制药公司建立桥梁，开启DT-109作为T2 D口服治疗药物的临床试验。

 DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is chronic disease characterized by high blood glucose and rapidly emerged as a global health care problem that threatens to reach pandemic levels by 2030. Nearly 350 million people worldwide are currently affected by diabetes. Diabetes is a major cause of heart disease and stroke and also leads to other complications, such as vision loss, kidney failure, and amputations of legs or feet. The effective drugs for treatment of T2D, such as insulin and glucagon-like peptide 1 (GLP- 1), require injections, which are inconvenient and expensive. Development of safer, more effective, and more convenient oral medicines, therefore, will be necessary for preventing the diabetes pandemic. The product of this SBIR is the oral dosage form of DT-109 for the treatment of T2D. DT-109 is a tripeptide that effectively lowered blood glucose in several T2D mouse models by increase the GLP-1 and insulin levels when orally administered. Since DT-109 is comprised of natural occurring L-amino acids, it is considered to be a safer, cheaper, and a convenient pharmaceutical intervention for T2D patients. The long-term goal of this SBIR is to complete preclinical development and identify a partner or investor consortium to fund clinical trials for DT-109 as an oral therapeutic for T2D. Diapin Therapeutics has demonstrated that DT-109 acts through a G-protein coupled receptor (GPCR) to elicit its activity and high throughput screening of GPCR libraries showed the 3 hits as an agonist among 160 GPCRs. This phase I hypothesis is that at least one of 3 GPCRs are essential for DT-109 to elicit its activity. There are two specific aims in this phase I SBIR proposal. Aim 1 is to confirm the results from high throughput screening and identify the specific GPCR(s) required for the effect using a gain-of-function model. Aim 2 is to determine the functional importance of the GPCR(s) using a loss-of-function model. Characterization of the MOA of DT-109 is critical for our understanding of the pharmacology of DT-109. The phase II of this SBIR will carry on the studies on pharmacokinetics/toxicokinetics and complete the data set for opening IND for DT-109. The patent for the oral dosage form of DT-109 has been issued and the identification of DT-109 targets will help us to bridge with big Pharmas to open clinical trials for DT-109 as an oral therapeutic for T2D.