title: PEGylation site-dependent structural heterogeneity study of monoPEGylated human parathyroid hormone fragment hPTH(1-34).
abstract: The structures of C- and N-terminally monoPEGylated human parathyroid hormone fragment hPTH(1-34) as well as their unmodified counterparts, poly(ethylene glycol) (PEG) and hPTH(1-34), have been studied by small-angle neutron scattering (SANS). The scattering results show that free hPTH(1-34) in 100 mM phosphate buffer (pH 7.4) aggregates into clusters. After conjugation with PEG, the PEG-peptide conjugates self-assemble into a supramolecular core-shell structure with a cylindrical shape. The PEG chains form a shell around the hPTH(1-34) core to shield hPTH(1-34) from the solvent. The detailed structural information on the self-assembled structures is extracted from SANS using a model of the cylindrical core with a shell of Gaussian chains attached to the core surface. On the basis of the data, because of the charge-dipole interactions between the conjugated PEG chain and the peptide, the conjugated PEG chain forms a more collapsed conformation compared to free PEG. Moreover, the size of the self-assembled structures formed by the C-terminally monoPEGylated hPTH(1-34) is about 3 times larger than that of the N-terminally monoPEGylated hPTH(1-34). The different aggregation numbers of the self-assembled structures, triggered by different PEGylation sites, are reported. These size discrepancies because of different PEGylation sites could potentially affect the pharmacokinetics of the hPTH(1-34) drug.
authors.affiliation: Department of Materials Science & Engineering, National Chiao Tung University , Hsinchu 30010, Taiwan.
authors.forename: Chih-Ying
authors.initials: CY
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Wen-Yih
authors.initials: WY
authors.lastname: Chen
authors.forename: Li-Chiao
authors.initials: LC
authors.lastname: Chang
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chen
authors.forename: Hsin-Lung
authors.initials: HL
authors.lastname: Chen
authors.forename: Ya-Sen
authors.initials: YS
authors.lastname: Sun
authors.forename: Hsiu-Yun
authors.initials: HY
authors.lastname: Lai
authors.forename: E-Wen
authors.initials: EW
authors.lastname: Huang
mesh_terms: D006801:Humans; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry*; D019379:Teriparatide / Q000737:chemistry*
chemical_list: D019379:Teriparatide; D011092:Polyethylene Glycols