title: A new reagent for stable thiol-specific conjugation.
abstract: Many clinically used protein therapeutics are modified to increase their efficacy. Example modifications include the conjugation of cytotoxic drugs to monoclonal antibodies or poly(ethylene glycol) (PEG) to proteins and peptides. Monothiol-specific conjugation can be efficient and is often accomplished using maleimide-based reagents. However, maleimide derived conjugates are known to be susceptible to exchange reactions with endogenous proteins. To address this limitation in stability, we have developed PEG-mono-sulfone 3, which is a latently reactive, monothiol selective conjugation reagent. Comparative reactions with PEG-maleimide and other common thiol-selective PEGylation reagents including vinyl sulfone, acrylate, and halo-acetamides show that PEG-mono-sulfone 3 undergoes more efficient conjugation under mild reaction conditions. Due to the latent reactivity of PEG-mono-sulfone 3, its reactivity can be tailored and, once conjugated, the electron-withdrawing ketone is easily reduced under mild conditions to prevent undesirable deconjugation and exchange reactions from occurring. We describe a comparative stability study demonstrating a PEG-maleimide conjugate to be more labile to deconjugation than the corresponding conjugate obtained using PEG-mono-sulfone 3.
authors: PolyTherics Ltd, The London Bioscience Innovation Centre , 2 Royal College Street, London NW1 0NH, U.K.
authors: George
authors: G
authors: Badescu
authors: Penny
authors: P
authors: Bryant
authors: Julia
authors: J
authors: Swierkosz
authors: Farzad
authors: F
authors: Khayrzad
authors: Estera
authors: E
authors: Pawlisz
authors: Monika
authors: M
authors: Farys
authors: Yuehua
authors: Y
authors: Cong
authors: Maurizio
authors: M
authors: Muroni
authors: Norbert
authors: N
authors: Rumpf
authors: Steve
authors: S
authors: Brocchini
authors: Antony
authors: A
authors: Godwin
mesh_terms: D006863:Hydrogen-Ion Concentration; D008301:Maleimides / Q000737:chemistry*; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry*
chemical_list: D008301:Maleimides; D013450:Sulfones; C043592:maleimide; D011092:Polyethylene Glycols