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

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.