A Comparative Study of Virucidal and Virustatic Multivalent Entry Inhibitors

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.