title: Synthetic erythropoietic proteins: tuning biological performance by site-specific polymer attachment.
abstract: Chemical synthesis in combination with precision polymer modification allows the systematic exploration of the effect of protein properties, such as charge and hydrodynamic radius, on potency using defined, homogeneous conjugates. A series of polymer-modified synthetic erythropoiesis proteins were constructed that had a polypeptide chain similar to the amino acid sequence of human erythropoietin but differed significantly in the number and type of attached polymers. The analogs differed in charge from +5 to -26 at neutral pH and varied in molecular weight from 30 to 54 kDa. All were active in an in vitro cell proliferation assay. However, in vivo potency was found to be strongly dependent on overall charge and size. The trends observed in this study may serve as starting points for the construction of more potent synthetic EPO analogs in the future.
authors.affiliation: Gryphon Therapeutics, 600 Gateway Boulevard, South San Francisco, California 94080, USA.
authors.forename: Shiah-Yun
authors.initials: SY
authors.lastname: Chen
authors.forename: Sonya
authors.initials: S
authors.lastname: Cressman
authors.forename: Feng
authors.initials: F
authors.lastname: Mao
authors.forename: Haiyan
authors.initials: H
authors.lastname: Shao
authors.forename: Donald W
authors.initials: DW
authors.lastname: Low
authors.forename: Hal S
authors.initials: HS
authors.lastname: Beilan
authors.forename: E Neil
authors.initials: EN
authors.lastname: Cagle
authors.forename: Maia
authors.initials: M
authors.lastname: Carnevali
authors.forename: Vincent
authors.initials: V
authors.lastname: Gueriguian
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Keogh
authors.forename: Heather
authors.initials: H
authors.lastname: Porter
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Stratton
authors.forename: M Con
authors.initials: MC
authors.lastname: Wiedeke
authors.forename: Laura
authors.initials: L
authors.lastname: Savatski
authors.forename: John W
authors.initials: JW
authors.lastname: Adamson
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Bozzini
authors.forename: Ada
authors.initials: A
authors.lastname: Kung
authors.forename: Stephen B H
authors.initials: SB
authors.lastname: Kent
authors.forename: James A
authors.initials: JA
authors.lastname: Bradburne
authors.forename: Gerd G
authors.initials: GG
authors.lastname: Kochendoerfer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000138:chemical synthesis / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008969:Molecular Sequence Data; D011108:Polymers / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011506:Proteins / Q000138:chemical synthesis* / Q000378:metabolism / Q000502:physiology; D051381:Rats
chemical_list: D011108:Polymers; D011506:Proteins; D004921:Erythropoietin