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De covalente a supramolecular: Repensando quimeras dirigidas a lisosomas a través del control de proximidad modular y

Nan Wang¹, Xiaoran Wang¹, Zhengyu Jiang¹

¹Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.

Chemistry (Weinheim an der Bergstrasse, Germany)

|February 20, 2026

Resumen

Este estudio introduce las interacciones huésped-huésped supramamiliares como una alternativa dinámica a los enlaces covalentes rígidos en biología química. Este enfoque permite sistemas moleculares adaptables con control sintonizable sobre las interacciones, particularmente para la orientación a lisosomas.

Área de la Ciencia:

Biología Química
Ingeniería Molecular
Bioquímica

Sus antecedentes:

Los enlaces covalentes en estrategias basadas en la proximidad ofrecen una adaptabilidad limitada debido a la estequiometría fija y al control estático.
Las arquitecturas moleculares rígidas dificultan las aplicaciones en entornos celulares dinámicos como el tráfico de lisosomas.

Objetivo del estudio:

Proponer las interacciones huésped-huésped supramamiliares como una alternativa modular y reversible a los enlaces covalentes.
Permitir el control dinámico sobre el ensamblaje molecular y la estequiometría para una adaptabilidad mejorada.
Ampliar los principios de diseño para modalidades basadas en la proximidad más allá de las conexiones covalentes estáticas.

Principales métodos:

Desarrollo de un marco conceptual para interfaces supramamiliares.
Análisis de las interacciones huésped-huésped para el ensamblaje molecular reversible.
Aplicación de principios a sistemas de degradación dirigidos a lisosomas.

Principales resultados:

La proximidad supramolecular permite el ensamblaje reversible y la estequiometría sintonizable.
Se logra la desacoplamiento del compromiso del objetivo del reclutamiento del efector.
Se introduce el control dinámico sobre los resultados de proximidad, mejorando la adaptabilidad.

Conclusiones:

Las interfaces supramamiliares representan una expansión significativa de la proximidad inducida químicamente.
Este enfoque ofrece nuevas vías para sistemas moleculares adaptables y controlables.
El marco proporciona principios de diseño generales para interacciones transitorias y dependientes del contexto.

Palabras clave:

molécula bifuncional sistema huésped-huésped proximidad inducida ensamblaje supramolecular

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