Monday, March 2, 2020

Systematic identification of engineered methionines and oxaziridines for efficient, stable, and site-specific antibody bioconjugation [@Toste_Group, @christhechang

Susanna K. Elledge, Hai L. Tran, Alec H. Christian, Veronica Steri, Byron Hann, F. Dean Toste, Christopher J. Chang, James A. Wells

Proceedings of the National Academy of Sciences 2020
DOI: 10.1073/pnas.1920561117

Site-specific chemical modification of proteins remains a critical need for bioconjugation. Here we explore the key parameters needed for efficient, selective, and stable modification of methionine using recently developed oxaziridine reagents, called ReACT. We systematically tested various oxaziridine compounds, and scanned accessible and buried sites in a therapeutic antibody for breast cancer to determine the chemical and structural parameters for most stable and efficient modification. We show these adducts are highly stable over days and can support the delivery of toxic payloads to regress tumors in animals. These studies on this important chemical modification expand our capability to site-specifically modify proteins and antibodies for many applications.

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

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