Effect of C-terminus Conjugation via Different Conjugation Chemistries on In Vivo Activity of Albumin-Conjugated Recombinant GLP-1
| Autor: | Kiyoon Min, Hyun-Woo Kim, Inchan Kwon, Junyong Park, Giyoong Tae, Jeong-Haeng Cho, Mijeong Bak |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
endocrine system
Pharmaceutical Science lcsh:RS1-441 02 engineering and technology in vivo glucose-lowering activity Article albumin conjugation law.invention lcsh:Pharmacy and materia medica 03 medical and health sciences In vivo law medicine Receptor 030304 developmental biology Alanine 0303 health sciences Chemistry digestive oral and skin physiology Albumin plasma half-life extension 021001 nanoscience & nanotechnology Human serum albumin body regions Biochemistry glucagon-like peptide-1 Glycine embryonic structures Recombinant DNA 0210 nano-technology medicine.drug Conjugate |
| Zdroj: | Pharmaceutics Pharmaceutics, Vol 13, Iss 263, p 263 (2021) Volume 13 Issue 2 |
| ISSN: | 1999-4923 |
| Popis: | Glucagon-like peptide-1 (GLP-1) is a peptide hormone with tremendous therapeutic potential for treating type 2 diabetes mellitus. However, the short half-life of its native form is a significant drawback. We previously prolonged the plasma half-life of GLP-1 via site-specific conjugation of human serum albumin (HSA) at position 16 of recombinant GLP-1 using site-specific incorporation of p-azido-phenylalanine (AzF) and strain-promoted azide-alkyne cycloaddition (SPAAC). However, the resulting conjugate GLP1_8G16AzF-HSA showed only moderate in vivo glucose-lowering activity, probably due to perturbed interactions with GLP-1 receptor (GLP-1R) caused by the albumin-linker. To identify albumin-conjugated GLP-1 variants with enhanced in vivo glucose-lowering activity, we investigated the conjugation of HSA to a C-terminal region of GLP-1 to reduce steric hindrance by the albumin-linker using two different conjugation chemistries. GLP-1 variants GLP1_8G37AzF-HSA and GLP1_8G37C-HSA were prepared using SPAAC and Michael addition, respectively. GLP1_8G37C-HSA exhibited a higher glucose-lowering activity in vivo than GLP1_8G16AzF-HSA, while GLP1_8G37AzF-HSA did not. Another GLP-1 variant, GLP1_8A37C-HSA, had a glycine to alanine mutation at position 8 and albumin at its C-terminus and exhibited in vivo glucose-lowering activity comparable to that of GLP1_8G37C-HSA, despite a moderately shorter plasma half-life. These results showed that site-specific HSA conjugation to the C-terminus of GLP-1 via Michael addition could be used to generate GLP-1 variants with enhanced glucose-lowering activity and prolonged plasma half-life in vivo. |
| Databáze: | OpenAIRE |
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