# Rational Design of Supramolecular Receptors for Consistent Binding Affinities under High-Salinity Conditions

## TL;DR

This paper introduces a new design for supramolecular receptors that maintain strong binding in high-salinity environments, improving their usefulness in biomedical applications.

## Contribution

The novel use of zwitterionic architectures eliminates self-ion pairing and external ion interference in supramolecular binding.

## Key findings

- Zwitterionic receptors eliminate self-ion pairing, making host concentration irrelevant to binding thermodynamics.
- Dual-charged hosts provide self-contained stabilization, shielding recognition sites from high-salinity interference.
- These receptors can encapsulate zwitterionic guests, overcoming challenges posed by strong aqueous solvation.

## Abstract

The
development of water-soluble multicharged macrocycles has opened
promising pathways in biomedical applications, enabling selective
molecular recognition for therapeutic and diagnostic uses. Yet, traditional
polyanionic and polycationic receptors often face performance limitations
under realistic operating conditions. A major drawback is the natural
tendency of these polycharged hosts to experience increasing screening
effects as concentration rises due to self-ion pairing phenomena,
which can reduce binding efficiency by several orders of magnitude.
These issues are further intensified when polyionic receptors are
used in high-salinity environments, typically used to replicate physiological
settings, where the abundance of ions introduces additional screening
effects that diminish the supramolecular affinity for a wide range
of guests. This study presents a new approach that leverages zwitterionic
synthetic receptors with rationally engineered architectures to overcome
these challenges. By incorporation of specific structural features,
self-ion pairing is eliminated, effectively making host concentration
no longer a controlling factor in the thermodynamics of the complexation
process. Additionally, these dual-charged hosts achieve self-contained
stabilization, naturally shielding recognition sites from external
ion interference under high-salinity conditions. Furthermore, the
ability of these supramolecular hosts to encapsulate zwitterionic
guests, a challenging task due to the strong solvation of these molecules
in aqueous solution, adds significant value to the functional versatility
of these macrocycles. Altogether, these findings represent a significant
advancement in the design of stable and adaptable receptor systems
for complex environments.