期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 135, 期 45, 页码 17223-17229出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja408868a
关键词
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资金
- Energy Biosciences Institute at University of California, Berkeley
- DOD Breast Cancer Research Program [BC016995]
- N.S.F
- Berkeley Chemical Biology Graduate Program (NRSA Training Grant) [I T32 GMO66698]
- Howard Hughes Medical Institute International Student Research Fellowship
- National Institutes of Health [IS 1S10RR022393-01]
The controlled attachment of synthetic groups to proteins is important for a number of fields, including therapeutics, where antibody drug conjugates are an emerging area of biologic medicines. We have previously reported a site-specific protein modification method using a transamination reaction that chemoselectively oxidizes the N-terminal amine of a polypeptide chain to a ketone or an aldehyde group. The newly introduced carbonyl can be used for conjugation to a synthetic group in one location through the formation of an oxime or a hydrazone linkage. To expand the scope of this reaction, we have used a combinatorial peptide library screening platform as a method to explore new transamination reagents while simultaneously identifying their optimal N-terminal sequences. N-Methylpyridinium-4-carboxaldehyde benzenesulfonate salt (Rapoport's salt, RS) was identified as a highly effective transamination reagent when paired with glutamate-terminal peptides and proteins. This finding establishes RS as a transamination reagent that is particularly well suited for antibody modification. Using a known therapeutic antibody, herceptin, it was demonstrated that RS can be used to modify the heavy chains of the wild-type antibody or to modify both the heavy and the light chains after N-terminal sequence mutation to add additional glutamate residues.
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