# A Comparative Study of Virucidal and Virustatic Multivalent Entry Inhibitors

## TL;DR

This paper compares how different chemical structures of multivalent entry inhibitors affect their ability to kill or just stop viruses from entering cells.

## Contribution

The study reveals that hydrophobic interactions with proteins determine whether an inhibitor is virucidal or virustatic.

## Key findings

- Sodium sulfonate MEIs showed virustatic effects, while sodium sulfate MEIs were virucidal.
- Hydrophobicity, measured by LogP and CMC, correlates with virucidal activity.
- Interactions with bovine serum albumin are linked to the virucidal mechanism.

## Abstract

Viral infections, such as those caused by herpes simplex
viruses
(HSV) and influenza, continue to pose a significant global health
challenge. We have focused on the development of multivalent entry
inhibitors (MEIs) that have an irreversible inhibition mechanism,
i.e., virucidal, as opposed to the commonly found reversible virustatic
ones. MEIs are typically composed of core structures connected to
multiple functional groups that are engineered to bind to viruses.
In between the core and the functional groups, we inserted alkyl linkers
and showed that such linkers, when long enough, were responsible for
a change in the inhibition mechanism by their hydrophobicity. In a
recent paper, we found that comparison of the antiviral properties
against HSV-2 of one pair of sulfonate and sulfate MEIs had led to
a surprising result. The compounds shared the same core (benzene)
and had three undecyl linkers that were terminated either by sodium
sulfates or by sodium sulfonates, respectively. The former showed
a virucidal and the latter a virustatic inhibition mechanism. In this
paper, we show that such a surprising difference is also true when
testing these compounds against HSV-1 and a few different influenza
strains. This difference remains when the hydrophobic linkers are
shorter (hexyl). For these four MEIs, we present a series of measurements
aimed at determining the hydrophobicity (critical micelle concentration
[CMC] and partition coefficient [LogP]) and their
binding with proteins. We find that the only parameters that correlate
positively with the virucidal mechanism are the interactions of the
compounds with bovine serum albumin and LogP. We
interpret our data as indicating that what matters for a virucidal
mechanism is the ability of a MEI to establish hydrophobic interactions
with proteins in solution.