期刊
NATURE CHEMISTRY
卷 11, 期 1, 页码 78-85出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41557-018-0154-0
关键词
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资金
- NIH [GM46059, F32GM108294, F32GM122204, F30HD093358, GM110535]
- MIT startup funds
- Damon Runyon Cancer Research Foundation Award
- Sontag Distinguished Scientist Award
- George Buchi Summer Research Fellowship
- Koch Graduate Fellowship in Cancer Research
- Bristol-Myers Squibb Fellowship in Synthetic Organic Chemistry
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [F30HD093358] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [F32GM122204, R37GM068649, R01GM046059, R35GM122483, R01GM110535] Funding Source: NIH RePORTER
Conjugates between proteins and small molecules enable access to a vast chemical space that is not achievable with either type of molecule alone; however, the paucity of specific reactions capable of functionalizing proteins and natural products presents a formidable challenge for preparing conjugates. Here we report a strategy for conjugating electron-rich (hetero) arenes to polypeptides and proteins. Our bioconjugation technique exploits the electrophilic reactivity of an oxidized selenocysteine residue in polypeptides and proteins, and the electron-rich character of certain small molecules to provide bioconjugates in excellent yields under mild conditions. This conjugation chemistry enabled the synthesis of peptide-vancomycin conjugates without the prefunctionalization of vancomycin. These conjugates have an enhanced in vitro potency for resistant Gram-positive and Gram-negative pathogens. Additionally, we show that a 6 kDa affibody protein and a 150 kDa immunoglobulin-G antibody could be modified without diminishing bioactivity.
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