Novel fatty acid chain modified GLP-1 derivatives with prolonged in vivo glucose-lowering ability and balanced glucoregulatory activity

Cai, Xingguang; Sun, Lin; Dai, Yuxuan; Avraham, Yosefa; Liu, Chunxia; Han, Jing; Liu, Yuan; Feng, Dazhi; Huang, Wenlong; Qian, Hai

doi:10.1016/j.bmc.2018.04.022

Cited by 12 publications

(4 citation statements)

References 15 publications

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“…24,25 Thus, considerable efforts have focused on improving the pharmacokinetic properties of GLP-1, such as modication of a fatty acid chain or polyethylene glycol (PEG), as well as linking to human albumin or Fc fragment. [26][27][28][29] Although the currently approved treatments with GLP-1R agonists exert remarkable antidiabetic effects, such as Exenatide or Semaglutide, further improvements on the GLP-1R agonists are still expected such as longer glucose control, better weight loss or more cardiovascular benets. 15,30 In addition, currently all the GLP-1R agonist drugs were developed according to the only two native GLP-1R agonists (GLP-1 and Exendin-4) which may induce severely homogenization and limit the development of more potential agents.…”

Section: Discussionmentioning

confidence: 99%

Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites

et al. 2020

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“…Covalent modification of peptides, proteins, and small-molecule drugs with fatty acids has been clinically and commercially successful . This is evidenced by the favorable pharmacokinetic properties demonstrated by several approved long-acting drugs, such as insulin detemir, insulin degludec, and fatty acid-modified analogs of GLP-1, namely, semaglutide and liraglutide. − …”

Section: Introductionmentioning

confidence: 99%

Enhancing Stability and Albumin Binding Efficiency of α-Conotoxin GI through Fatty Acid Modification

Qi,

He,

Zhang

et al. 2023

Biochemistry

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α-Conotoxin GI is a competitive blocker of muscle-type acetylcholine receptors and holds the potential for being developed as a molecular probe or a lead compound for drug discovery. In this study, four fatty acid-modified α-conotoxin GI analogues of different lengths were synthesized by using a fatty acid modification strategy. Then, we performed a series of in vitro stability assays, albumin binding assays, and pharmacological activity assays to evaluate these modified mutants. The experimental results showed that the presence of fatty acids significantly enhanced the in vitro stability and albumin binding ability of α-conotoxin GI and that this effect was proportional to the length of the fatty acids used. Pharmacological activity tests showed that the modified mutants maintained a good acetylcholine receptor antagonistic activity. The present study shows that fatty acid modification can be an effective strategy to significantly improve conotoxin stability and albumin binding efficiency while maintaining the original targeting ion channel activity.

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“…It is mainly used in the following aspects: (1) Improve the stability of peptides. The hypoglycemic peptide drug liraglutide is modified by fatty acids to form a reversible complex with serum albumin, 25 which greatly prolongs the absorption time of the drug in the body and increases the half-life of the peptide drug in vivo; erythropoietin, by introducing sugar chains containing sialic acid, can effectively extend the half-life of polypeptide drugs in the body. 26 (2) Enhance the cell targeting of peptides.…”

Section: ■ Introductionmentioning

confidence: 99%

Glucose–Lipopeptide Conjugates Reveal the Role of Glucose Modification Position in Complexation and the Potential of Malignant Melanoma Therapy

Zhao

Zhang

et al. 2021

J. Med. Chem.

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Glycosylation and fatty acid modification are promising strategies to improve peptide performance. We previously studied glycosylation and fatty acid modification of the anticancer peptide R-lycosin-I. In this study, we further investigated the comodification of fatty acids and monosaccharides in R-lycosin-I. A glucose derivative was covalently coupled to the ε-amino group of the Lys residues of the lipopeptide R-C 12 , which was derived from R-lycosin-I modified with dodecanoic acid, and obtained seven glycolipid peptides. They exhibited different cytotoxicity profiles, which may be related to the changes in physicochemical properties and binding ability to glucose transporter 1 (GLUT1). Among them, R-C 12 -4 exhibited the highest cytotoxicity and improved selectivity. A further study demonstrated that R-C 12 -4 showed significant cytotoxicity and antimetastasis activity in murine melanoma cells, melanoma spheroids, and animal models. Our results indicated that the glucose derivative modification position plays important roles in glucose−lipopeptide conjugates, and R-C 12 -4 might be a promising lead for developing anticancer drugs.

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Novel fatty acid chain modified GLP-1 derivatives with prolonged in vivo glucose-lowering ability and balanced glucoregulatory activity

Cited by 12 publications

References 15 publications

Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites

Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites

Enhancing Stability and Albumin Binding Efficiency of α-Conotoxin GI through Fatty Acid Modification

Glucose–Lipopeptide Conjugates Reveal the Role of Glucose Modification Position in Complexation and the Potential of Malignant Melanoma Therapy

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