{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:31:48Z","timestamp":1787063508779,"version":"build-2736575974"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,1,8]],"date-time":"2018-01-08T00:00:00Z","timestamp":1515369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20150243"],"award-info":[{"award-number":["BK20150243"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20161028"],"award-info":[{"award-number":["BK20161028"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81602960"],"award-info":[{"award-number":["81602960"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81602964"],"award-info":[{"award-number":["81602964"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2018,2]]},"abstract":"\n Background and Purpose<\/jats:title>\n \n Incretin\u2010based therapies based on glucagon\u2010like peptide\u20101 (GLP\u20101) receptor agonists are effective treatments of type 2 diabetes. Abundant research has focused on the development of long\u2010acting GLP\u20101 receptor agonists. However, all GLP\u20101 receptor agonists in clinical use or development are based on human or\n Gila<\/jats:italic>\n GLP\u20101. We have identified a potent GLP\u20101 receptor agonist, xGLP\u20101B, based on\n Xenopus<\/jats:italic>\n GLP\u20101.\n <\/jats:p>\n <\/jats:sec>\n \n Experimental Approach<\/jats:title>\n \n To further modify the structure of xGLP\u20101B, alanine scanning was performed to study the structure \u2010activity relationship of xGLP\u20101B. Two strategies were then employed to improve bioactivity. First, the C\u2010terminal tail of lixisenatide was appended to cysteine\u2010altered xGLP\u20101B analogues. Second, polyethylene glycol (PEG) chains with different molecular weights were conjugated with the peptides, giving a series of PEGylated conjugates. Comprehensive bioactivity studies of these conjugates were performed\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n From the\n in vitro<\/jats:italic>\n receptor activation potency and\n in vivo<\/jats:italic>\n acute hypoglycaemic activities of conjugates\n 25<\/jats:bold>\n \u2010\n 36<\/jats:bold>\n ,\n 33<\/jats:bold>\n was identified as the best candidate for further biological assessments. Conjugate\n 33<\/jats:bold>\n exhibited prominent hypoglycaemic and insulinotropic activities, as well as improved pharmacokinetic profiles\n in vivo<\/jats:italic>\n . The prolonged antidiabetic duration of\n 33<\/jats:bold>\n was further confirmed by pre\u2010oral glucose tolerance tests (OGTT) and multiple OGTT. Furthermore, chronic treatment of\n db\/db<\/jats:italic>\n mice with\n 33<\/jats:bold>\n ameliorated non\u2010fasting blood glucose and insulin levels, reduced HbA1c values and normalized their impaired glucose tolerance. Importantly, no\n in vivo<\/jats:italic>\n toxicity was observed in mice treated with\n 33<\/jats:bold>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Implications<\/jats:title>\n \n Peptide\n 33<\/jats:bold>\n is a promising long\u2010acting type 2 diabetes therapeutic deserving further investigation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bph.14107","type":"journal-article","created":{"date-parts":[[2017,11,24]],"date-time":"2017-11-24T03:09:13Z","timestamp":1511492953000},"page":"544-557","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Xenopus<\/i>\n \u2010derived glucagon\u2010like peptide\u20101 and polyethylene\u2010glycosylated glucagon\u2010like peptide\u20101 receptor agonists: long\u2010acting hypoglycaemic and insulinotropic activities with potential therapeutic utilities"],"prefix":"10.1111","volume":"175","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5605-1868","authenticated-orcid":false,"given":"Jing","family":"Han","sequence":"first","affiliation":[{"name":"School of Chemistry and Materials Science Jiangsu Normal University Xuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Fei","sequence":"additional","affiliation":[{"name":"School of Chemistry and Materials Science Jiangsu Normal University Xuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Chemistry and Materials Science Jiangsu Normal University Xuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chemistry and Materials Science Jiangsu Normal University Xuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Materials Science Jiangsu Normal University Xuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Materials Science Jiangsu Normal University Xuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2741-7469","authenticated-orcid":false,"given":"Junjie","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy Nanjing Medical University Nanjing China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,1,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)37366-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-016-0709-0"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13878"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2013.09.016"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6RA22648E"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12856"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00174"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1935"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2017.03.018"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.05.012"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm4017448"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12843"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.03.032"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.15.7915"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.04.021"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc100404x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.605592"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm500810s"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm900752a"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12955"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2012.140"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-017-0846-0"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm100602m"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc08-9025"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1037"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2016.04.016"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.2016.1123249"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.6b00787"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201600374"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5OB00333D"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp5002685"}],"container-title":["British 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