Kapcan Eden, Krygier Karolina, da Luz Maya, Serniuck Nickolas J, Zhang Ali, Bramson Jonathan, Rullo Anthony F
Center for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada.
Nat Commun. 2025 Mar 24;16(1):2855. doi: 10.1038/s41467-025-58083-z.
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.
一类特殊的诱导邻近性的双功能分子/嵌合体，即所谓的分子胶，利用正协同作用来稳定三元复合物的形成并诱导生物学反应。尽管分子胶具有实用性，但合理设计它们仍然具有挑战性。在诱导细胞-细胞邻近性的情况下尤其如此，这涉及到由非相互作用或负相互作用蛋白质组成的三元复合物。在这项工作中，我们开发了一种双邻近标记策略，使嵌合体能够在三元复合物内将非相互作用的血清抗体与肿瘤表面蛋白共价交联。由此产生的对解离的抗性，包括在存在竞争性结合配体的情况下，模拟了分子胶的稳定作用。我们证明这些共价胶模拟物（CGM）可以在肿瘤-免疫识别的三个不同模型系统中诱导细胞-细胞邻近性，从而导致显著的功能增强。总的来说，这项工作强调了双近端共价标记作为一种潜在的通用策略的实用性，该策略可稳定由非相互作用蛋白质组成的三元复合物并加强细胞-细胞相互作用。
