Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability

Yu Seok Youn; Su Young Chae; Seulki Lee; Jae Eun Jeon; Hyong Goo Shin; Kang Choon Lee

doi:10.1016/j.bcp.2006.09.013

Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability

Yu Seok Youn
, Su Young Chae
, Seulki Lee
, Jae Eun Jeon
, Hyong Goo Shin
, Kang Choon Lee

Department of Pharmacy

Sungkyunkwan University
Korea Institute of Science and Technology

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

Abstract

PEGylation has been considered to be a good biotechnique for improving the therapeutic value of glucagon-like peptide-1 (GLP-1) analogs for the treatment of type 2 diabetes. Despite the attractive anti-diabetic potentials, GLP-1 does not exert its full biological action because of its extremely short life-time in vivo due to rapid proteolytic degradation. Here, the enzyme-resistant mono-PEGylated GLP-1 isomers substituted at Lys²⁶- or Lys³⁴-amine were prepared through a newly devised site-specific PEGylation process using a maleic anhydride-protection/deprotection method. The therapeutic potentials of these site-specific PEGylated GLP-1 isomers (Lys²⁶- or Lys³⁴-PEG-GLP-1) along with His⁷-(N-terminus) PEG-GLP-1 were evaluated by examining their insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Lys³⁴-PEG-GLP-1 was found to have the well-preserved insulinotropic activity (93% efficacy versus GLP-1) in isolated rat pancreatic islets. Furthermore, Lys³⁴-PEG-GLP-1 showed the most prominent glucose-stabilizing capability, evaluated via an oral glucose tolerance test in db/db mice by considering the following three crucial factors: (i) maximum blood glucose level (BGL), (ii) required time to lower the BGL below 100 mg/dl, and (iii) total hypoglycemic degree. Additionally, Lys³⁴-PEG-GLP-1 had longer half-lives than the other PEGylated GLP-1s in the dipeptidyl peptidase IV (DPP IV) inhibitor-treated liver or kidney homogenate, and its stability against DPP IV was also comparable to that of Lys²⁶-PEG-GLP-1. Taken together, Lys³⁴-PEG-GLP-1 displayed the promising characteristics in all evaluations versus His⁷- or Lys²⁶-PEG-GLP-1. This site-specific PEGylated GLP-1 analog would have therapeutic usefulness for treating type 2 diabetes on account of the well-preserved insulinotropic activity, the increased proteolytic stability, and thereby the improved glucose-stabilizing capability.

Original language	English
Pages (from-to)	84-93
Number of pages	10
Journal	Biochemical Pharmacology
Volume	73
Issue number	1
DOIs	https://doi.org/10.1016/j.bcp.2006.09.013
State	Published - 1 Jan 2007

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Dipeptidyl peptidase-IV
Glucagons-like peptide-1
Neutral endopeptidase 24.11
PEGylation
Type-2 diabetes

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10.1016/j.bcp.2006.09.013

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Youn, Y. S., Chae, S. Y., Lee, S., Jeon, J. E., Shin, H. G., & Lee, K. C. (2007). Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Biochemical Pharmacology, 73(1), 84-93. https://doi.org/10.1016/j.bcp.2006.09.013

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title = "Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability",

abstract = "PEGylation has been considered to be a good biotechnique for improving the therapeutic value of glucagon-like peptide-1 (GLP-1) analogs for the treatment of type 2 diabetes. Despite the attractive anti-diabetic potentials, GLP-1 does not exert its full biological action because of its extremely short life-time in vivo due to rapid proteolytic degradation. Here, the enzyme-resistant mono-PEGylated GLP-1 isomers substituted at Lys26- or Lys34-amine were prepared through a newly devised site-specific PEGylation process using a maleic anhydride-protection/deprotection method. The therapeutic potentials of these site-specific PEGylated GLP-1 isomers (Lys26- or Lys34-PEG-GLP-1) along with His7-(N-terminus) PEG-GLP-1 were evaluated by examining their insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Lys34-PEG-GLP-1 was found to have the well-preserved insulinotropic activity (93\% efficacy versus GLP-1) in isolated rat pancreatic islets. Furthermore, Lys34-PEG-GLP-1 showed the most prominent glucose-stabilizing capability, evaluated via an oral glucose tolerance test in db/db mice by considering the following three crucial factors: (i) maximum blood glucose level (BGL), (ii) required time to lower the BGL below 100 mg/dl, and (iii) total hypoglycemic degree. Additionally, Lys34-PEG-GLP-1 had longer half-lives than the other PEGylated GLP-1s in the dipeptidyl peptidase IV (DPP IV) inhibitor-treated liver or kidney homogenate, and its stability against DPP IV was also comparable to that of Lys26-PEG-GLP-1. Taken together, Lys34-PEG-GLP-1 displayed the promising characteristics in all evaluations versus His7- or Lys26-PEG-GLP-1. This site-specific PEGylated GLP-1 analog would have therapeutic usefulness for treating type 2 diabetes on account of the well-preserved insulinotropic activity, the increased proteolytic stability, and thereby the improved glucose-stabilizing capability.",

keywords = "Dipeptidyl peptidase-IV, Glucagons-like peptide-1, Neutral endopeptidase 24.11, PEGylation, Type-2 diabetes",

author = "Youn, \{Yu Seok\} and Chae, \{Su Young\} and Seulki Lee and Jeon, \{Jae Eun\} and Shin, \{Hyong Goo\} and Lee, \{Kang Choon\}",

year = "2007",

month = jan,

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doi = "10.1016/j.bcp.2006.09.013",

language = "English",

volume = "73",

pages = "84--93",

journal = "Biochemical Pharmacology",

issn = "0006-2952",

publisher = "Elsevier Inc.",

number = "1",

}

Youn, YS, Chae, SY, Lee, S, Jeon, JE, Shin, HG & Lee, KC 2007, 'Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability', Biochemical Pharmacology, vol. 73, no. 1, pp. 84-93. https://doi.org/10.1016/j.bcp.2006.09.013

Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. / Youn, Yu Seok; Chae, Su Young; Lee, Seulki et al.
In: Biochemical Pharmacology, Vol. 73, No. 1, 01.01.2007, p. 84-93.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment

T2 - Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability

AU - Youn, Yu Seok

AU - Chae, Su Young

AU - Lee, Seulki

AU - Jeon, Jae Eun

AU - Shin, Hyong Goo

AU - Lee, Kang Choon

PY - 2007/1/1

Y1 - 2007/1/1

N2 - PEGylation has been considered to be a good biotechnique for improving the therapeutic value of glucagon-like peptide-1 (GLP-1) analogs for the treatment of type 2 diabetes. Despite the attractive anti-diabetic potentials, GLP-1 does not exert its full biological action because of its extremely short life-time in vivo due to rapid proteolytic degradation. Here, the enzyme-resistant mono-PEGylated GLP-1 isomers substituted at Lys26- or Lys34-amine were prepared through a newly devised site-specific PEGylation process using a maleic anhydride-protection/deprotection method. The therapeutic potentials of these site-specific PEGylated GLP-1 isomers (Lys26- or Lys34-PEG-GLP-1) along with His7-(N-terminus) PEG-GLP-1 were evaluated by examining their insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Lys34-PEG-GLP-1 was found to have the well-preserved insulinotropic activity (93% efficacy versus GLP-1) in isolated rat pancreatic islets. Furthermore, Lys34-PEG-GLP-1 showed the most prominent glucose-stabilizing capability, evaluated via an oral glucose tolerance test in db/db mice by considering the following three crucial factors: (i) maximum blood glucose level (BGL), (ii) required time to lower the BGL below 100 mg/dl, and (iii) total hypoglycemic degree. Additionally, Lys34-PEG-GLP-1 had longer half-lives than the other PEGylated GLP-1s in the dipeptidyl peptidase IV (DPP IV) inhibitor-treated liver or kidney homogenate, and its stability against DPP IV was also comparable to that of Lys26-PEG-GLP-1. Taken together, Lys34-PEG-GLP-1 displayed the promising characteristics in all evaluations versus His7- or Lys26-PEG-GLP-1. This site-specific PEGylated GLP-1 analog would have therapeutic usefulness for treating type 2 diabetes on account of the well-preserved insulinotropic activity, the increased proteolytic stability, and thereby the improved glucose-stabilizing capability.

AB - PEGylation has been considered to be a good biotechnique for improving the therapeutic value of glucagon-like peptide-1 (GLP-1) analogs for the treatment of type 2 diabetes. Despite the attractive anti-diabetic potentials, GLP-1 does not exert its full biological action because of its extremely short life-time in vivo due to rapid proteolytic degradation. Here, the enzyme-resistant mono-PEGylated GLP-1 isomers substituted at Lys26- or Lys34-amine were prepared through a newly devised site-specific PEGylation process using a maleic anhydride-protection/deprotection method. The therapeutic potentials of these site-specific PEGylated GLP-1 isomers (Lys26- or Lys34-PEG-GLP-1) along with His7-(N-terminus) PEG-GLP-1 were evaluated by examining their insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Lys34-PEG-GLP-1 was found to have the well-preserved insulinotropic activity (93% efficacy versus GLP-1) in isolated rat pancreatic islets. Furthermore, Lys34-PEG-GLP-1 showed the most prominent glucose-stabilizing capability, evaluated via an oral glucose tolerance test in db/db mice by considering the following three crucial factors: (i) maximum blood glucose level (BGL), (ii) required time to lower the BGL below 100 mg/dl, and (iii) total hypoglycemic degree. Additionally, Lys34-PEG-GLP-1 had longer half-lives than the other PEGylated GLP-1s in the dipeptidyl peptidase IV (DPP IV) inhibitor-treated liver or kidney homogenate, and its stability against DPP IV was also comparable to that of Lys26-PEG-GLP-1. Taken together, Lys34-PEG-GLP-1 displayed the promising characteristics in all evaluations versus His7- or Lys26-PEG-GLP-1. This site-specific PEGylated GLP-1 analog would have therapeutic usefulness for treating type 2 diabetes on account of the well-preserved insulinotropic activity, the increased proteolytic stability, and thereby the improved glucose-stabilizing capability.

KW - Dipeptidyl peptidase-IV

KW - Glucagons-like peptide-1

KW - Neutral endopeptidase 24.11

KW - PEGylation

KW - Type-2 diabetes

UR - https://www.scopus.com/pages/publications/33845207048

U2 - 10.1016/j.bcp.2006.09.013

DO - 10.1016/j.bcp.2006.09.013

M3 - Article

C2 - 17054919

AN - SCOPUS:33845207048

SN - 0006-2952

VL - 73

SP - 84

EP - 93

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

IS - 1

ER -

Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability

Abstract

UN SDGs

Keywords

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