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Pyrazolone ligation-mediated versatile sequential bioconjugations

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Abstract

Bioconjugation chemistries are critical tools in biotherapeutics discovery. The past efforts have been exclusively focused on two-segment conjugations. However, emerging research directions, such as polypharmacy biotherapeutics, desire multiple-component bioconjugations where more than two pharmacologically related biomolecules can be assembled into a single construct in high efficiency. We present here a set of sequential bioconjugation chemistries centered on a pyrazolone structural motif. It starts with a clickable “pyrazolone ligation” between a hydrazine group and a β-ketoester moiety followed by the conjugation between the newly formed pyrazolone core and an aldehyde-bearing biomolecule through a Knoevenagel reaction forming a Michael addition acceptor that can effectively capture a thiol-bearing biomolecule. When utilized intermolecularly, it quickly assembles four segments together forming a quadruple functional construct. When applied intramolecularly, it offers a set of highly diverse biomolecule scaffolds including stapled peptides and poly-macrocyclic peptides. We envision broad utilities of such sequential ligation chemistries.

Graphical abstract: Pyrazolone ligation-mediated versatile sequential bioconjugations

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Article information


Submitted
30 Apr 2020
Accepted
23 Jun 2020
First published
24 Jun 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Pyrazolone ligation-mediated versatile sequential bioconjugations

M. Mailig and F. Liu, Chem. Sci., 2020, Advance Article , DOI: 10.1039/D0SC02466J

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