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Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones

Due to their exquisite cysteine-selectivity, excellent stability, and ability to functionally rebridge disulfide bonds, dibromopyridazinediones are emerging as an exciting new class of bioconjugation reagents, particularly in the field of antibody conjugation. Despite this, relatively little work ha...

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Autores principales: Bahou, Calise, Richards, Daniel A., Maruani, Antoine, Love, Elizabeth A., Javaid, Faiza, Caddick, Stephen, Baker, James R., Chudasama, Vijay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058253/
https://www.ncbi.nlm.nih.gov/pubmed/29405223
http://dx.doi.org/10.1039/c7ob03138f
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author Bahou, Calise
Richards, Daniel A.
Maruani, Antoine
Love, Elizabeth A.
Javaid, Faiza
Caddick, Stephen
Baker, James R.
Chudasama, Vijay
author_facet Bahou, Calise
Richards, Daniel A.
Maruani, Antoine
Love, Elizabeth A.
Javaid, Faiza
Caddick, Stephen
Baker, James R.
Chudasama, Vijay
author_sort Bahou, Calise
collection PubMed
description Due to their exquisite cysteine-selectivity, excellent stability, and ability to functionally rebridge disulfide bonds, dibromopyridazinediones are emerging as an exciting new class of bioconjugation reagents, particularly in the field of antibody conjugation. Despite this, relatively little work has been performed on the optimisation of their synthesis and subsequent reaction with immunoglobulins. Herein we present a novel synthetic route towards functionalised dibromopyridazinediones, proceeding via an isolatable dibromopyridazinedione-NHS ester. Reaction of this activated intermediate with a variety of amines produces functional dibromopyridazinediones in good to excellent yields. The disulfide rebridging capacity of these reagents was optimised on the clinically relevant IgG1 trastuzumab, resulting in a general method which allows for the generation of site-selectively modified native trastuzumab with over 90% homogeneity (no disulfide scrambling) without the need for protein engineering or enzymatic conjugation.
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spelling pubmed-60582532018-08-08 Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones Bahou, Calise Richards, Daniel A. Maruani, Antoine Love, Elizabeth A. Javaid, Faiza Caddick, Stephen Baker, James R. Chudasama, Vijay Org Biomol Chem Chemistry Due to their exquisite cysteine-selectivity, excellent stability, and ability to functionally rebridge disulfide bonds, dibromopyridazinediones are emerging as an exciting new class of bioconjugation reagents, particularly in the field of antibody conjugation. Despite this, relatively little work has been performed on the optimisation of their synthesis and subsequent reaction with immunoglobulins. Herein we present a novel synthetic route towards functionalised dibromopyridazinediones, proceeding via an isolatable dibromopyridazinedione-NHS ester. Reaction of this activated intermediate with a variety of amines produces functional dibromopyridazinediones in good to excellent yields. The disulfide rebridging capacity of these reagents was optimised on the clinically relevant IgG1 trastuzumab, resulting in a general method which allows for the generation of site-selectively modified native trastuzumab with over 90% homogeneity (no disulfide scrambling) without the need for protein engineering or enzymatic conjugation. Royal Society of Chemistry 2018-02-28 2018-01-29 /pmc/articles/PMC6058253/ /pubmed/29405223 http://dx.doi.org/10.1039/c7ob03138f Text en This journal is © The Royal Society of Chemistry 2018 http://creativecommons.org/licenses/by/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0)
spellingShingle Chemistry
Bahou, Calise
Richards, Daniel A.
Maruani, Antoine
Love, Elizabeth A.
Javaid, Faiza
Caddick, Stephen
Baker, James R.
Chudasama, Vijay
Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones
title Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones
title_full Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones
title_fullStr Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones
title_full_unstemmed Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones
title_short Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones
title_sort highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058253/
https://www.ncbi.nlm.nih.gov/pubmed/29405223
http://dx.doi.org/10.1039/c7ob03138f
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