title: The molecular basis for the prolonged blood circulation of lipidated incretin peptides: Peptide oligomerization or binding to serum albumin?
abstract: Hybrid incretin peptides are a new generation of drugs for the treatment of diabetes and obesity. Despite their biological potency, the effectiveness of these peptides as drugs is limited by their short circulation time in blood (typically within minutes). In this work, we show that lipid conjugated forms of a GLP-1/GIP/glucagon hybrid peptides stay in circulation for hours. We studied the oligomerization and albumin-binding of the unconjugated hybrid peptide as well as its lipidated variants. These lipidated peptides differ in the N-terminal mutation, the position of lipidation and the linkage to lipid. We found that these lipidated peptides form stable oligomers at concentrations above 1mg/mL. This concentration range is relevant to formulation and storage of the peptides. We observed no binding between the peptide oligomers and human serum albumin. However, at the expected therapeutic concentration range (~10-100ng/mL), the oligomers dissociate into monomers. The monomers of lipidated peptides bind to albumin. We have determined the dissociation constants of binding between the lipidated peptides and serum albumin. The dissociation constants of albumin-binding of our lipidated peptides are all very close and similar to that of the fatty acid binding of albumin. Our findings suggest that the monomeric lipidated peptides bind to HSA mainly by the fatty acid chain. Therefore, albumin binding is likely to be a universal mechanism of the prolonged circulating duration of lipidated pharmaceutical peptides.
authors: Materials Processing Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: wangyy@uncw.edu.
authors: Ying
authors: Y
authors: Wang
authors: Materials Processing Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors: Aleksey
authors: A
authors: Lomakin
authors: Therapuetic Modality, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors: Sonoko
authors: S
authors: Kanai
authors: Therapuetic Modality, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors: Rainer
authors: R
authors: Alex
authors: Pharmaceutical Science, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors: Sara
authors: S
authors: Belli
authors: Pharmaceutical Science, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors: Massimiliano
authors: M
authors: Donzelli
authors: Materials Processing Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Department of Physics, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA; Center for Materials Science and Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors: George B
authors: GB
authors: Benedek
mesh_terms: D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000097:blood* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D054795:Incretins / Q000097:blood* / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D011485:Protein Binding; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism*; D013997:Time Factors
chemical_list: D054795:Incretins; D012709:Serum Albumin; D052216:Glucagon-Like Peptide 1
keywords: Albumin binding; GLP1; Incretin; Lipidated peptide; Oligomerization; Surface plasmon resonance