Poly-L-lysine Glycoconjugates Inhibit DC-SIGN-mediated Attachment of Pandemic Viruses

Envelope glycoproteins of many viruses are heavily glycosylated. Among other functions, virus glycans can mediate interactions with host receptors and contribute to internalization and virus dissemination. The C-type lectin receptor DC-SIGN, which is expressed by cells of the innate immune system, can act as an entry receptor for pathogens, including pandemic viruses such as SARS-CoV-2, ebola, and HIV. In the context of the recent SARS-CoV-2 pandemic, this mechanism has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral envelope glycoproteins has therefore the potential to generate broad spectrum antivirulent agents. Moreover, the important role of this mechanism in numerous viral infections, as well as an interaction partner conserved in the host genome highlight the potential of DC-SIGN-targeted therapeutics not only for the treatment of existing infections, but also for the rapid response to future pandemics with newly emerging virus serotypes. Here, we demonstrate that mannose-functionalized poly-L-lysine glycoconjugates efficiently inhibit the attachment of viral glycoproteins from SARS-CoV-2, ebola, and HIV to DC-SIGN-presenting cells with up to picomolar affinity. Treatment of susceptible cells leads to prolonged receptor internalization and statistically significant inhibition of virus binding for up to 6 h. Furthermore, the polymers are fully biocompatible and readily cleared by the target cells. Finally, the thermodynamic analysis of these multivalent interactions revealed an entropy-driven affinity enhancement, opening promising perspectives for the future development of multivalent therapeutics.