General dual functionalisation of biomacromolecules via a cysteine bridging strategy

Site-selective modification of peptides and proteins has resulted in the development of a host of novel tools for the study of cellular systems or the synthesis of enhanced biotherapeutics. There is a need for useful methodologies that enable site-selective modification of native peptides or protein...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2020-06, Vol.18 (22), p.4224-4230
Main Authors: Walsh, Stephen J, Iegre, Jessica, Seki, Hikaru, Bargh, Jonathan D, Sore, Hannah F, Parker, Jeremy S, Carroll, Jason S, Spring, David R
Format: Article
Language:English
Subjects:
Antibodies
Biological activity
Biomolecules
Cell Line, Tumor
Cell Survival - drug effects
Cysteine - chemistry
Cytotoxicity
Fluorescent dyes
Fluorescent indicators
Humans
Macromolecular Substances - chemical synthesis
Macromolecular Substances - chemistry
Macromolecular Substances - pharmacology
Models, Molecular
Molecular Structure
Payloads
Peptides
Proteins
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Trastuzumab - pharmacology
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Summary:Site-selective modification of peptides and proteins has resulted in the development of a host of novel tools for the study of cellular systems or the synthesis of enhanced biotherapeutics. There is a need for useful methodologies that enable site-selective modification of native peptides or proteins, which is even more prevalent when modification of the biomolecule with multiple payloads is desired. Herein, we report the development of a novel dual functional divinylpyrimidine (dfDVP) platform that enables robust and modular modification of peptides, antibody fragments and antibodies. These biomacromolecules could be easily functionalised with a range of functional payloads (e.g. fluorescent dyes, cytotoxic warheads or cell-penetrating tags). Importantly, the dual functionalised peptides and antibodies demonstrated exquisite bioactivity in a range of in vitro cellular assays, showcasing the enhanced utility of these bioactive conjugates.
ISSN:1477-0520
1477-0539
DOI:10.1039/d0ob00907e