Salt Effect Accelerates Site-Selective Cysteine Bioconjugation

Peng Dai; Chi Zhang; Matthew Welborn; James J Shepherd; Tianyu Zhu; Troy Van Voorhis; Bradley L Pentelute

doi:10.1021/acscentsci.6b00180

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Salt Effect Accelerates Site-Selective Cysteine Bioconjugation

Journal article

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Salt Effect Accelerates Site-Selective Cysteine Bioconjugation

Peng Dai, Chi Zhang, Matthew Welborn, James J Shepherd, Tianyu Zhu, Troy Van Voorhis and Bradley L Pentelute

ACS central science, Vol.2(9), pp.637-646

09/28/2016

DOI: 10.1021/acscentsci.6b00180

PMCID: PMC5043432

PMID: 27725962

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https://doi.org/10.1021/acscentsci.6b00180View

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Abstract

Highly efficient and selective chemical reactions are desired. For small molecule chemistry, the reaction rate can be varied by changing the concentration, temperature, and solvent used. In contrast for large biomolecules, the reaction rate is difficult to modify by adjusting these variables because stringent biocompatible reaction conditions are required. Here we show that adding salts can change the for an arylation bioconjugation reaction between a cysteine residue within a four-residue sequence (π-clamp) and a perfluoroaryl electrophile. Biocompatible ammonium sulfate significantly enhances the reaction rate without influencing the site-specificity of π-clamp mediated arylation, enabling the fast synthesis of two site-specific antibody-drug conjugates that selectively kill HER2-positive breast cancer cells. Computational and structure-reactivity studies indicate that salts may tune the reaction rate through modulating the interactions between the π-clamp hydrophobic side chains and the electrophile. On the basis of this understanding, the salt effect is extended to other bioconjugation chemistry, and a new regioselective alkylation reaction at π-clamp cysteine is developed.

Details

Title: Subtitle: Salt Effect Accelerates Site-Selective Cysteine Bioconjugation
Creators: Peng Dai - Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
Chi Zhang - Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
Matthew Welborn - Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
James J Shepherd - Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
Tianyu Zhu - Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
Troy Van Voorhis - Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
Bradley L Pentelute - Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
Resource Type: Journal article
Publication Details: ACS central science, Vol.2(9), pp.637-646
DOI: 10.1021/acscentsci.6b00180
PMID: 27725962
PMCID: PMC5043432
NLM abbreviation: ACS Cent Sci
ISSN: 2374-7943
eISSN: 2374-7951
Publisher: United States
Grant note: S10 OD016326 / NIH HHS R01 GM110535 / NIGMS NIH HHS
Language: English
Date published: 09/28/2016
Academic Unit: Chemistry
Record Identifier: 9984001176402771

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