Issue 24, 2023

Sequence-defined antibody-recruiting macromolecules

Abstract

Antibody-recruiting molecules represent a novel class of therapeutic agents that mediate the recruitment of endogenous antibodies to target cells, leading to their elimination by the immune system. Compared to single-ligand copies, macromolecular scaffolds presenting multiple copies of an antibody-binding ligand offer advantages in terms of increased complex avidity. In this study, we describe the synthesis of sequence-defined macromolecules designed for antibody recruitment, utilising dinitrophenol (DNP) as a model antibody-recruiting motif. The use of discrete macromolecules gives access to varying the spacing between DNP motifs while maintaining the same chain length. This characteristic enables the investigation of structure-dependent binding interactions with anti-DNP antibodies. Through solid-phase thiolactone chemistry, we synthesised a series of oligomers with precisely localised DNP motifs along the backbone and a terminal biotin motif for surface immobilisation. Utilising biolayer interferometry analysis, we observed that oligomers with adjacent DNP motifs exhibited enhanced avidity for anti-DNP antibodies. Molecular modelling provided insights into the structures and dynamics of the various macromolecules, shedding light on the accessibility of the ligands to the antibodies. Overall, our findings highlight that the use of sequence-defined macromolecules can contribute to our understanding of structure–activity relationships and provide insights for the design of novel antibody-recruiting therapeutic agents.

Graphical abstract: Sequence-defined antibody-recruiting macromolecules

Supplementary files

Article information

Article type
Edge Article
Submitted
22 mar 2023
Accepted
22 may 2023
First published
22 may 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 6572-6578

Sequence-defined antibody-recruiting macromolecules

R. Aksakal, C. Tonneaux, A. Uvyn, M. Fossépré, H. Turgut, N. Badi, M. Surin, B. G. De Geest and Filip. E. Du Prez, Chem. Sci., 2023, 14, 6572 DOI: 10.1039/D3SC01507F

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