# Supramolecules for Pathogen Inhibition: From Polymers to Self-Assembled Nanosystems

## TL;DR

Researchers developed self-assembled supramolecules that can broadly inhibit viruses by mimicking natural mucus barriers and adapting to viral mutations.

## Contribution

A new class of self-assembled supramolecular nanosystems is introduced for broad-spectrum antiviral inhibition.

## Key findings

- Supramolecular nanosystems show broad-spectrum antiviral activity against HSV, SARS-CoV-2, and IAV.
- These nanosystems adapt to viral mutations by dynamically presenting binding moieties to spike proteins.
- They provide steric shielding and low toxicity while preventing virus-host cell interactions.

## Abstract

Vaccines and antivirals have
been developed to combat virus infection,
but they face the challenges of rapid and unpredictable virus mutations,
which have been widely observed during COVID-19. An alternative approach
is, therefore, highly needed as an additional tool to prevent virus
infection. As the infection of a virus usually starts by binding to
its receptor, preventing virus interaction with host cells has been
considered as a promising method and has been explored by various
multivalent polymeric structures. However, like small-molecule pharmaceuticals,
these carefully engineered polymeric structures rarely sustain broad-spectrum
efficacy, because viral proteins are morphologically diverse and evolve
rapidly, enabling resistance to polymeric inhibitors through mutations
in receptor-binding domains (RBDs). To address these challenges, our
group developed and investigated a new class of virus inhibitors based
on self-assembled supramolecules. These nanosystems are built by noncovalent
conjugation of small molecules or oligomers through hydrophobic interactions,
π-π stacking, hydrogen bonding, electrostatic interactions,
and so on. By carefully balancing the molecular geometry and directional
forces, nanostructures of different dimensions (nanofiber, nanodisk,
nanosheet, nanomicelle, etc.) are obtained and functionalized with
binding groups to virus spike proteins inspired by mucins, which are
natural polymers forming the mucus hydrogel to prevent virus infection.
By using different functional building blocks, it is possible to build
heteromutlivalent nanostructures through noncovalent synthesis targeting
multiple binding domains simultaneously. Distinct from covalent polymeric
structures, the dynamic nature of self-assembled nanosystems allows
functional groups to automatically locate complementary binding pockets
on viral spike protein, thereby adapting to mutation-driven RBD changes
through the adaptive presentation of binding moieties. Besides binding
to virus spike protein, these nanosystems also provide steric shielding
of virus particles to prevent virus interaction with host cells. These
supramolecular nanosystems exhibit low toxicity and broad-spectrum
antiviral activity against viruses that use distinct binding receptors,
including herpes simplex virus (HSV; sulfate binding), SARS-CoV-2
(sulfate binding), and influenza A virus (IAV; sialic acid binding).
To forward the application of these nanosystems, their stability should
be carefully evaluated, as diverse factors in physiological conditions
could affect the self-assembly of the supramolecules. Although they
have been proven to be stable in cell culture conditions, a deep investigation
into biological systems is still necessary. One approach to improved
stability might be introducing additional reversible bonds. Besides,
translating these systems will require comprehensive biosafety and
bioactivity evaluation and continued chemical innovation. Collectively,
these findings demonstrate the feasibility of broad-spectrum antiviral
inhibitors based on supramolecular assemblies and may open new routes
to design broad-spectrum virus inhibitors to assist the combat with
pathogens.