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<p>A special class of proximity inducing bifunctional molecules/chimeras called molecular glues leverage positive co-operativity to stabilize ternary complex formation and induce a biological response. Despite their utility, molecular glues remain challenging to rationally design. This is particularly true in the context of inducing cell-cell proximity which involve ternary complexes that comprise non- or negatively interacting proteins. In this work, we develop a dual proximity labeling strategy enabling a chimera to covalently crosslink a non-interacting serum antibody to a tumor surface protein, within a ternary complex. The resultant resistance to dissociation, including in the presence of competitor binding ligands, mimics molecular glue stabilization. We demonstrate these covalent glue mimics (CGMs) can induce cell-cell proximity in three distinct model systems of tumor-immune recognition, leading to significant functional enhancements. Collectively, this work underscores the utility of dual proximal covalent labeling as a potential general strategy to stabilize ternary complexes comprising non-interacting proteins and enforce cell-cell interactions.</p>

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Mimicry of molecular glues using dual covalent chimeras

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月24日

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  • Eden Kapcan,
  • Karolina Krygier,
  • Maya da Luz,
  • Nickolas J. Serniuck,
  • Ali Zhang,
  • Jonathan Bramson,
  • Anthony F. Rullo

摘要

A special class of proximity inducing bifunctional molecules/chimeras called molecular glues leverage positive co-operativity to stabilize ternary complex formation and induce a biological response. Despite their utility, molecular glues remain challenging to rationally design. This is particularly true in the context of inducing cell-cell proximity which involve ternary complexes that comprise non- or negatively interacting proteins. In this work, we develop a dual proximity labeling strategy enabling a chimera to covalently crosslink a non-interacting serum antibody to a tumor surface protein, within a ternary complex. The resultant resistance to dissociation, including in the presence of competitor binding ligands, mimics molecular glue stabilization. We demonstrate these covalent glue mimics (CGMs) can induce cell-cell proximity in three distinct model systems of tumor-immune recognition, leading to significant functional enhancements. Collectively, this work underscores the utility of dual proximal covalent labeling as a potential general strategy to stabilize ternary complexes comprising non-interacting proteins and enforce cell-cell interactions.