title: A novel glucagon-like peptide 1 peptide identified from Ophisaurus harti.
abstract: Glucagon-like peptide 1 receptor (GLP1R) is a promising target for the treatment of type 2 diabetes. Because of the short half-life of endogenous GLP1 peptide, other GLP1R agonists are considered to be appealing therapeutic candidates. A high-throughput assay has been established to screen for GLP1R agonists in a 60 000-well natural product compound library fractionated from 670 different herbs/materials widely used in traditional Chinese medicines (TCMs). The screening is based on primary screen of GLP1R⁺ reporter gene assay with the counter screen in GLP1R⁻ cell line. An active fraction, A089-147, was identified from the screening. Fraction A089-147 was isolated from dried Ophisaurus harti, and the fact that its GLP1R agonist activity was sensitive to trypsin treatment indicates its peptidic nature. The active ingredient of A089-147 was later identified as O. harti GLP1 through transcriptome analysis. Chemically synthesized O. harti GLP1 showed GLP1R agonist activity and sensitivity to dipeptidase IV digestion. This study illustrated a comprehensive screening strategy to identify novel GLP1R agonists from TCMs libraries and at the same time underlined the difficulty of identifying a non-peptidic GLP1R agonist. The novel O. harti GLP1 peptide yielded from this study confirmed broader application of TCMs libraries in active peptide identification.
authors.affiliation: Institutes for Advanced Interdisciplinary Research, East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhu
authors.forename: Xian
authors.initials: X
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Bao
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Hu
authors.forename: Gang
authors.initials: G
authors.lastname: Xia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D041981:Gastrointestinal Tract / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008116:Lizards / Q000378:metabolism*; D008516:Medicine, Chinese Traditional; D008969:Molecular Sequence Data; D059748:Proteolysis; D018027:Receptors, Glucagon / Q000819:agonists*; D030162:Reptilian Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020539:Sequence Analysis, Protein; D054852:Small Molecule Libraries; D059467:Transcriptome
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D030162:Reptilian Proteins; D054852:Small Molecule Libraries; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: GLP1; GLP1R; High throughput screening; Ophisaurus harti; TCM; transcriptome; type 2 diabetes