Design of Multivalent Inhibitors for Preventing Cellular Uptake

Veronika Schubertová,Veronika Schubertová,Veronika Schubertová,Robert Vácha,Robert Vácha,Robert Vácha,Francisco J Martinez-Veracoechea

doi:10.1038/s41598-017-11735-7

Abstract

Cellular entry, the first crucial step of viral infection, can be inhibited by molecules adsorbed on the virus surface. However, apart from using stronger affinity, little is known about the properties of such inhibitors that could increase their effectiveness. Our simulations showed that multivalent inhibitors can be designed to be much more efficient than their monovalent counterparts. For example, for our particular simulation model, a single multivalent inhibitor spanning 5 to 6 binding sites is enough to prevent the uptake compared to the required 1/3 of all the receptor binding sites needed to be blocked by monovalent inhibitors. Interestingly, multivalent inhibitors are more efficient in inhibiting the uptake not only due to their increased affinity but mainly due to the co-localization of the inhibited receptor binding sites at the virion’s surface. Furthermore, we show that Janus-like inhibitors do not induce virus aggregation. Our findings may be generalized to other uptake processes including bacteria and drug-delivery.

Highlights

Nano-inhibitors that can selectively target viruses and prevent them from infecting cells could be a game changer in the development of antiviral therapeutics and could have a huge impact in the treatment of challenging diseases caused by viruses like Dengue, Influenza, Ebola, and Zika[1,2]
In the present study we show that multivalent inhibitors can provide additional advantages besides super-selectivity and increased affinity: they can be designed for spatially correlated targeting of receptor binding sites (RBS) on the virus capsid
We investigated the process of spontaneous receptor mediated endocytosis where the capsid is closely wrapped by the membrane

Summary

Introduction

Nano-inhibitors that can selectively target viruses and prevent them from infecting cells could be a game changer in the development of antiviral therapeutics and could have a huge impact in the treatment of challenging diseases caused by viruses like Dengue, Influenza, Ebola, and Zika[1,2]. One way to prevent viral infection is by developing inhibitors that can effectively and selectively bind to the virus capsid before they can bind to the cell membrane receptors and stop the internalization. The virus is wrapped by the membrane In this process, the bending energy needs to be compensated by the interaction with receptors and can be stabilized by protein assemblies[3,4,5,6,7,8,9,10,11,12,13,14]. In the present study we show that multivalent inhibitors can provide additional advantages besides super-selectivity and increased affinity: they can be designed for spatially correlated targeting of RBSs on the virus capsid. We demonstrate that Janus multivalent inhibitors (with inhibitors on one side and inert on the other side) could be the best option for preventing inhibitor-bridged aggregation and uptake of capsids (see Fig. 1)

Methods

Results

Conclusion