Glycosaminoglycan Conjugation for Improving the Duration of Therapeutic Action of Glucagon-Like Peptide-1

Ichikawa, Makiko; Hirayama, Tetsuya; Fukushima, Masanobu; Kitazawa, Ikue; Kojima, Kazuhiro; Sakai, Tokiko; Takatsu, Yoshihiro; Ohtaki, Tetsuya

doi:10.1021/acsomega.8b00467

“…This effect is observed in both the Fu et al [45] and McVicar, Rayavara & Carney [47] studies where the mean halflife of the conjugated peptide increased as the size of PEG increased. In contrast, the highest comparative effect was recorded in the Ichikawa et al [35] work conjugating GLP-1 with 50 kDa heparosan (Fig 2). In this instance, the conjugated peptide conferred an absolute mean difference of 33.55 h (Table 3).…”

Section: Comparison Of Effect Sizesmentioning

confidence: 82%

“…In contrast, the highest comparative effect was recorded in the Ichikawa et al . [ 35 ] work conjugating GLP-1 with 50 kDa heparosan ( Fig 2 ). In this instance, the conjugated peptide conferred an absolute mean difference of 33.55 h ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Details of all 16 studies are given in the supplementary material (S2 Table ), while the studies that included comparable controls were further analysed as detailed in the next section. Some of the peptides captured in the group of 16 were well-studied native peptides like insulin and glucagon-like peptide 1 (GLP-1) [32][33][34][35][36]. Others were novel, heterologous peptides like PN-2921, an interleukin-6 binding peptide derived from a helix-loop-helix scaffold identified through phage display [37].…”

Section: Data Overviewmentioning

confidence: 99%

See 1 more Smart Citation

Conjugates for use in peptide therapeutics: A systematic review and meta-analysis

Wijesinghe

¹

,

Kumari

²

,

Booth

³

2022

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While peptides can be excellent therapeutics for several conditions, their limited in vivo half-lives have been a major bottleneck in the development of therapeutic peptides. Conjugating the peptide to an inert chemical moiety is a strategy that has repeatedly proven to be successful in extending the half-life of some therapeutics. This systematic review and meta-analysis was conducted to examine the available literature and assess it in an unbiased manner to determine which conjugates, both biological and synthetic, provide the greatest increase in therapeutic peptide half-life. Systematic searches run on PubMed, Scopus and SciFinder databases resulted in 845 studies pertaining to the topic, 16 of these were included in this review after assessment against pre-specified inclusion criteria registered on PROSPERO (#CRD42020222579). The most common reasons for exclusion were non-IV administration and large peptide size. Of the 16 studies that were included, a diverse suite of conjugates that increased half-life from 0.1 h to 33.57 h was identified. Amongst these peptides, the largest increase in half-life was seen when conjugated with glycosaminoglycans. A meta-analysis of studies that contained fatty acid conjugates indicated that acylation contributed to a statistically significant extension of half-life. Additionally, another meta-analysis followed by a sensitivity analysis suggested that conjugation with specifically engineered recombinant peptides might contribute to a more efficient extension of peptide half-life as compared to PEGylation. Moreover, we confirmed that while polyethylene glycol is a good synthetic conjugate, its chain length likely has an impact on its effectiveness in extending half-life. Furthermore, we found that most animal studies do not include as much detail when reporting findings as compared to human studies. Inclusion of additional experimental detail on aspects such as independent assessment and randomization may be an easily accomplished strategy to drive more conjugated peptides towards clinical studies.

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“…This effect is observed in both the Fu et al (45) and McVicar, Rayavara & Carney (47) studies where the mean half-life of the conjugated peptide increased as the size of PEG increased. In contrast, the highest comparative effect was recorded in the Ichikawa et al (35) work conjugating GLP-1 with 50 kDa heparosan (Fig 2). In this instance, the conjugated peptide conferred an absolute mean difference of 33.55 h (Table 3).…”

Section: Comparison Of Effect Sizesmentioning

confidence: 82%

Conjugates for use in peptide therapeutics: a systematic review and meta-analysis

Wijesinghe

¹

,

Kumari

²

,

Booth

³

2021

Preprint

View full text Add to dashboard Cite

While peptides can be excellent therapeutics for several conditions, their limited in vivo half-lives have been a major bottleneck in the development of therapeutic peptides. Conjugating the peptide to an inert chemical moiety is a strategy that has repeatedly proven to be successful in extending the half-life of some therapeutics. This systematic review and meta-analysis was conducted to examine the available literature and assess it in an unbiased manner to determine which conjugates, both biological and synthetic, provide the greatest increase in therapeutic peptide half-life. Systematic searches run on PubMed, Scopus and SciFinder databases resulted in 845 studies pertaining to the topic, 16 of these were included in this review after assessment against pre-specified inclusion criteria registered on PROSPERO (#CRD42020222579). The most common reasons for exclusion were non-IV administration and large peptide size. Of the 16 studies that were included, a diverse suite of conjugates that increased half-life from 0.1 h to 33.57 h was identified. Amongst these peptides, the largest increase in half-life was seen when conjugated with glycosaminoglycans. A meta-analysis of studies that contained fatty acid conjugates indicated that acylation contributed to a statistically significant extension of half-life. Additionally, another meta-analysis followed by a sensitivity analysis suggested that conjugation with specifically engineered recombinant peptides might contribute to a more efficient extension of peptide half-life as compared to PEGylation. Moreover, we confirmed that while polyethylene glycol is a good synthetic conjugate, its chain length likely has an impact on its effectiveness in extending half-life. Furthermore, we found that most animal studies do not include as much detail when reporting findings as compared to human studies. Inclusion of additional experimental detail on aspects such as independent assessment and randomization may be an easily accomplished strategy to drive more conjugated peptides towards clinical studies.

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“…For reprints contact: weda-h@weda-h.org of the small intestine, which promotes the β cells of the pancreas to secrete insulin after food intake. 4,8,9 GLP-1 analogue has become a second-line therapeutic drug for T2DM treatment. 10,11 GLP-1 analogue, Exendin-4 (Ex-4), has been used in clinical treatment of type 2 diabetes mellitus (T2DM).…”

Section: Introductionmentioning

confidence: 99%

Exendin-4 improves glucose metabolism in insulin-resistant cells by upregulating the phosphorylative AMPK

Li¹,

Gong²,

Qu³

et al. 2019

JAH

0

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Glucagon-like peptide-1 (GLP-1) is a peptide with multiple functions in regulating blood glucose with the mechnism still not throughly understand. AMP-activated protein kinase (AMPK) plays an important role in glucose and energy homeostasis, especially in type 2 diabetes mellitus (T2DM) pathophysiology. This study explores GLP-1 analogue exendin-4 (Ex-4) regulating glucose balance by activating AMPK and regulation gluconeogenesis in insulin-resistant cell model (IR/ HepG2). IR/HepG2 cells were treated with Ex-4, AMPK activator or Ex-4 pretreated with AMPK inhibitor Compound C. The change of cell morphology, glucose consumption and lipid content in IR/HepG2 cells were examined. The expression of AMPK and p-AMPK in IR/HepG2 treated by Ex-4 were determined by Western blot and immunochemisthistology (IHC) assay. Key enzymes of glucose metabolism, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) in IR/HepG2 cells treated by Ex-4 were detected by Western blot, immunohistochemistry and qRT-PCR. The results showed that Ex-4 treatment increased the expression of p-AMPK and reduced the expression of G-6-Pase and PEPCK in IR/HepG2 cells. Pretreatment with AMPK inhibitor Compound C counteracts the effect of Ex-4. These findings suggest that Ex-4 fulfilled it glucose regulation effect by phosphorylation of AMPK and decreased the expression of enzymes involving gluconeogenesis.

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Glycosaminoglycan Conjugation for Improving the Duration of Therapeutic Action of Glucagon-Like Peptide-1

Cited by 11 publications

References 44 publications

Conjugates for use in peptide therapeutics: A systematic review and meta-analysis

Conjugates for use in peptide therapeutics: A systematic review and meta-analysis

Conjugates for use in peptide therapeutics: a systematic review and meta-analysis

Exendin-4 improves glucose metabolism in insulin-resistant cells by upregulating the phosphorylative AMPK

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