title: Effect of PEG Architecture on the Hybridization Thermodynamics and Protein Accessibility of PEGylated Oligonucleotides.
abstract: PEGylation is an attractive approach to modifying oligonucleotides intended for therapeutic purposes. PEG conjugation reduces protein interactions with the oligonucleotide, and helps to overcome their intrinsic biopharmaceutical shortcomings, such as poor enzymatic stability, rapid body clearance, and unwanted immunostimulation. However, the effect of PEG architecture and the manner in which the PEG component interferes with the hybridization of the oligonucleotide remain poorly understood. In this study, we systematically compare the hybridization thermodynamics and protein accessibility of several DNA conjugates involving linear, Y-shaped, and brush-type PEG. It is found that PEGylated DNA experiences two opposing effects: local excluded volume effect and chemical interactions, the strengths of which are architecture-dependent. Notably, the brush architecture is able to offer significantly greater protein shielding capacity than its linear or Y-shaped counterparts, while maintaining nearly identical free energy for DNA hybridization compared with free DNA.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Jia
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA.
authors.forename: Dali
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
mesh_terms: D004247:DNA / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D009693:Nucleic Acid Hybridization; D009841:Oligonucleotides / Q000737:chemistry* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D013816:Thermodynamics; D044366:Transition Temperature
chemical_list: D009841:Oligonucleotides; D011092:Polyethylene Glycols; D004247:DNA
keywords: PEGylation; bioconjugates; hybridization thermodynamics; oligonucleotides; polymers