Supramolecular Polymer‐Surfactant Co‐Assemblies for Multivalent HSV‐1 Inhibition

ABSTRACT Supramolecular assemblies are of fundamental importance for cellular life and bio‐interactive materials. The structure and function of these assemblies are decisively influenced by the design of their molecular components. In this work, we present a modular synthetic strategy for six novel bio‐functional surfactants with a sulfonate headgroup (termed SupraVir surfactants). These amphiphilic molecules were designed for strong interactions with viral envelope proteins, virus inhibition, and to co‐assemble water‐soluble benzene‐1,3,5‐tricarboxamide derivatives (BTAs) to generate surfactant‐grafted supramolecular polymers. Systematic spectroscopic and microscopic studies showed that the morphology of the co‐assemblies strongly depends on the surfactant‐BTA ratio. At surfactant ratios higher than 1, the native BTA nanofibers were disrupted, resulting in micellar architectures. In the test with herpes simplex virus (HSV‐1), fibrous supramolecular polymers show significantly lower half‐maximal inhibitory concentrations (IC 50 ) compared to the corresponding micellar aggregates of the pure surfactants. Interestingly, the co‐assemblies exhibited lower cytotoxicity than the functional surfactants alone, probably due to their structured incorporation into the polymeric scaffold. The dynamics of the co‐assemblies, probed by hydrogen‐deuterium exchange mass spectrometry (HDX‐MS), showed correlations to the effectiveness. These results demonstrate a new co‐assembly strategy of functional positioning antiviral surfactants in supramolecular scaffolds for the development of multivalent antiviral materials.