Albumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications

Current study was conducted to design and screen a long-lasting Exendin-4 analog for treating type 2 diabetes via the novel strategy of albumin binding combined with thrombin enzymolysis. Firstly, a series of fusion peptides, containing different albumin-binding tags, a determinate thrombin-cleavabl...

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Autores principales:	Shujuan Xu, Fang Wang, Hui Li, Ya Wang, Dongzhong Fang
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	albumin-binding thrombin exendin-4 long-acting controlled-release type 2 diabetes diabetic complications Biotechnology TP248.13-248.65
Acceso en línea:	https://doaj.org/article/afad88e87b4d4802b9a0a4bd3de12f00
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spelling	oai:doaj.org-article:afad88e87b4d4802b9a0a4bd3de12f002021-11-04T15:51:54ZAlbumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications2165-59792165-598710.1080/21655979.2021.1995993https://doaj.org/article/afad88e87b4d4802b9a0a4bd3de12f002021-10-01T00:00:00Zhttp://dx.doi.org/10.1080/21655979.2021.1995993https://doaj.org/toc/2165-5979https://doaj.org/toc/2165-5987Current study was conducted to design and screen a long-lasting Exendin-4 analog for treating type 2 diabetes via the novel strategy of albumin binding combined with thrombin enzymolysis. Firstly, a series of fusion peptides, containing different albumin-binding tags, a determinate thrombin-cleavable linker and a native Exendin-4, were prepared via chemosynthesis for in vitro and in vivo characterization. Surface plasmon resonance (SPR) assay, thrombin cleavage assay and plasma stability test were performed for screening the optimal HEX peptide with enhanced albumin-binding affinity, controlled-release as well as plasma stability. The in vivo anti-diabetic efficacies of the selected candidate were further assessed via both acute and chronic pharmacodynamic evaluation in diabetic model animals. HEX15 exhibited either the highest affinity for human serum albumin or the superior in vitro stability and controlled release of Exendin-4 among twenty-one HEX peptides. Glucose tolerance test and hypoglycemic duration assay both revealed the notably improved the glucose tolerance and prolonged normoglycemic duration, respectively, of diabetic mice after single treatment of HEX15. Furthermore, chronic dosing of HEX15 significantly ameliorated the manifestations of diabetes in the db/db mice, including body weight, food intake, glycometabolism as well as hyperlipaemia. Interestingly, combination therapy of HEX15 and long non-coding RNA-ENST00000411554 notably accelerated the wound healing and improved foot ulcer symptoms in model rats with diabetic foot ulcers. In summary, based on the strategy of linking the heptapeptide tag and thrombin-based sustained release, a long-acting Exendin-4 analogue, HEX15, holds potential to be developed as a drug for ameliorating T2D as well as diabetic complications.Shujuan XuFang WangHui LiYa WangDongzhong FangTaylor & Francis Grouparticlealbumin-bindingthrombinexendin-4long-actingcontrolled-releasetype 2 diabetesdiabetic complicationsBiotechnologyTP248.13-248.65ENBioengineered, Vol 0, Iss 0 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	albumin-binding thrombin exendin-4 long-acting controlled-release type 2 diabetes diabetic complications Biotechnology TP248.13-248.65
spellingShingle	albumin-binding thrombin exendin-4 long-acting controlled-release type 2 diabetes diabetic complications Biotechnology TP248.13-248.65 Shujuan Xu Fang Wang Hui Li Ya Wang Dongzhong Fang Albumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications
description	Current study was conducted to design and screen a long-lasting Exendin-4 analog for treating type 2 diabetes via the novel strategy of albumin binding combined with thrombin enzymolysis. Firstly, a series of fusion peptides, containing different albumin-binding tags, a determinate thrombin-cleavable linker and a native Exendin-4, were prepared via chemosynthesis for in vitro and in vivo characterization. Surface plasmon resonance (SPR) assay, thrombin cleavage assay and plasma stability test were performed for screening the optimal HEX peptide with enhanced albumin-binding affinity, controlled-release as well as plasma stability. The in vivo anti-diabetic efficacies of the selected candidate were further assessed via both acute and chronic pharmacodynamic evaluation in diabetic model animals. HEX15 exhibited either the highest affinity for human serum albumin or the superior in vitro stability and controlled release of Exendin-4 among twenty-one HEX peptides. Glucose tolerance test and hypoglycemic duration assay both revealed the notably improved the glucose tolerance and prolonged normoglycemic duration, respectively, of diabetic mice after single treatment of HEX15. Furthermore, chronic dosing of HEX15 significantly ameliorated the manifestations of diabetes in the db/db mice, including body weight, food intake, glycometabolism as well as hyperlipaemia. Interestingly, combination therapy of HEX15 and long non-coding RNA-ENST00000411554 notably accelerated the wound healing and improved foot ulcer symptoms in model rats with diabetic foot ulcers. In summary, based on the strategy of linking the heptapeptide tag and thrombin-based sustained release, a long-acting Exendin-4 analogue, HEX15, holds potential to be developed as a drug for ameliorating T2D as well as diabetic complications.
format	article
author	Shujuan Xu Fang Wang Hui Li Ya Wang Dongzhong Fang
author_facet	Shujuan Xu Fang Wang Hui Li Ya Wang Dongzhong Fang
author_sort	Shujuan Xu
title	Albumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications
title_short	Albumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications
title_full	Albumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications
title_fullStr	Albumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications
title_full_unstemmed	Albumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications
title_sort	albumin-binding tag derived exendin-4 analogue for treating hyperglycemia and diabetic complications
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/afad88e87b4d4802b9a0a4bd3de12f00
work_keys_str_mv	AT shujuanxu albuminbindingtagderivedexendin4analoguefortreatinghyperglycemiaanddiabeticcomplications AT fangwang albuminbindingtagderivedexendin4analoguefortreatinghyperglycemiaanddiabeticcomplications AT huili albuminbindingtagderivedexendin4analoguefortreatinghyperglycemiaanddiabeticcomplications AT yawang albuminbindingtagderivedexendin4analoguefortreatinghyperglycemiaanddiabeticcomplications AT dongzhongfang albuminbindingtagderivedexendin4analoguefortreatinghyperglycemiaanddiabeticcomplications
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Albumin-binding tag derived Exendin-4 analogue for treating hyperglycemia and diabetic complications

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