title: Variant fatty acid-like molecules Conjugation, novel approaches for extending the stability of therapeutic peptides.
abstract: The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides.
authors.affiliation: Tianjin Neurological Institute, Tianjin Medical University General Hospital, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Tianjin Institute of Pharmaceutical Research, China.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tianjin Institute of Pharmaceutical Research, China.
authors.forename: Qunchao
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Tianjin Institute of Pharmaceutical Research, China.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Tianjin Institute of Pharmaceutical Research, China.
authors.forename: Lida
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Pharmacy, Tianjin Medical University, Tianjin, China.
authors.forename: Dexin
authors.initials: D
authors.lastname: Kong
authors.affiliation: Tianjin Institute of Pharmaceutical Research, China.|Department of Pharmacy, Tianjin Medical University, Tianjin, China.|Department of Oncology, University of Oxford, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Gong
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D010455:Peptides / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D010455:Peptides; D011498:Protein Precursors; D012709:Serum Albumin; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4