Abstract
Exendin-4 is a strong therapeutic candidate for the treatment of metabolic syndrome. Related receptor agonist drugs have been on the market since 2005. However, technical limitations and the pain caused by subcutaneous injection have severely limited patient compliance. The goal of the study is to investigate a biologically active exendin-4 analog could be administered orally. Using intraperitoneal glucose tolerance tests, we discovered that exendin4-cysteine administered by oral gavage had a distinct hypoglycemic effect in C57BL/6J mice. Using Rosetta Design and Amber, we designed and screened a series of exendin4-cysteine analogs to identify those that retained biological activity while resisting trypsin digestion. Trypsin Cleavage Site Mutated Exendin4-cysteine 1 (TSME-1), an analog whose bioactivity was similar to exendin-4 and was almost completely resistant to trypsin, was screened out. In addition, TSME-1 significantly normalized the blood glucose levels and the availability of TSME-1 was significantly higher than that of exendin-4 and exendin4-cysteine. Collectively orally administered TSME-1, a trypsin-resistant exendin-4 analog obtained by the system, is a strong candidate for future treatments of type 2 diabetes.
Highlights
Metabolic disorders, including type 2 diabetes (T2D), obesity, hyperlipidemia, and hypertension, affect millions of people worldwide
Using intraperitoneal glucose tolerance tests, we discovered that exendin4-cysteine administered by oral gavage had a distinct hypoglycemic effect in C57BL/6J mice
Trypsin Cleavage Site Mutated Exendin4-cysteine 1 (TSME-1), an analog whose bioactivity was similar to exendin-4 and was almost completely resistant to trypsin, was screened out
Summary
Metabolic disorders, including type 2 diabetes (T2D), obesity, hyperlipidemia, and hypertension, affect millions of people worldwide. The need for additional drugs or alternative treatments that are administered has become an urgent issue in biomedical research. Since its identification by Nauck in 1986 [3], increasing evidence has demonstrated various biological functions of GLP-1 through the activation of the glucagon-like peptide-1 receptor (GLP-1R). These roles include improving insulin biosynthesis and secretion, inhibiting glucagon secretion, suppressing appetite, and increasing the insulin sensitivity of the liver and peripheral tissues [4]. Advances in the research of GLP-1 have provided a new approach to the treatment of metabolic disorder-related symptoms [5,6,7]. Since 2005, Bydureon®, Victoza®, Eperzan® and other GLP-1 analog drugs have joined an extensive list of existing drugs, indicating the importance and favorable research prospects of related candidates [10,11,12]
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