A New Reagent for Stable Thiol-Specific Conjugation

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• 作者：George Badescu ; Penny Bryant ; Julia Swierkosz ; Farzad Khayrzad ; Estera Pawlisz ; Monika Farys ; Yuehua Cong ; Maurizio Muroni ; Norbert Rumpf ; Steve Brocchini ; Antony Godwin
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：March 19, 2014
• 年：2014
• 卷：25
• 期：3
• 页码：460-469
• 全文大小：384K
• 年卷期：v.25,no.3(March 19, 2014)
• ISSN：1520-4812

文摘

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鈥搈ono-sulfone 3, which is a latently reactive, monothiol selective conjugation reagent. Comparative reactions with PEG鈥搈aleimide and other common thiol-selective PEGylation reagents including vinyl sulfone, acrylate, and halo-acetamides show that PEG鈥搈ono-sulfone 3 undergoes more efficient conjugation under mild reaction conditions. Due to the latent reactivity of PEG鈥搈ono-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鈥搈aleimide conjugate to be more labile to deconjugation than the corresponding conjugate obtained using PEG鈥搈ono-sulfone 3.