title: Size dependence of steric shielding and multivalency effects for globular binding inhibitors.
abstract: Competitive binding inhibitors based on multivalent nanoparticles have shown great potential for preventing virus infections. However, general design principles of highly efficient inhibitors are lacking as the quantitative impact of factors such as virus concentration, inhibitor size, steric shielding, or multivalency effects in the inhibition process is not known. Based on two complementary experimental inhibition assays we determined size-dependent steric shielding and multivalency effects. This allowed us to adapt the Cheng-Prusoff equation for its application to multivalent systems. Our results show that the particle and volume normalized IC50 value of an inhibitor at very low virus concentration predominantly depends on its multivalent association constant, which itself exponentially increases with the inhibitor/virus contact area and ligand density. Compared to multivalency effects, the contribution of steric shielding to the IC50 values is only minor, and its impact is only noticeable if the multivalent dissociation constant is far below the virus concentration, which means if all inhibitors are bound to the virus. The dependence of the predominant effect, either steric shielding or multivalency, on the virus concentration has significant implications on the in vitro testing of competitive binding inhibitors and determines optimal inhibitor diameters for the efficient inhibition of viruses.
authors.affiliation: Institute of Chemistry and Biochemistry, †Institute of Theoretical Physics, and §Research Centre of Electron Microscopy and Core Facility BioSupraMol, Institute of Chemistry and Biochemistry, Freie Universität Berlin , Berlin, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vonnemann
authors.forename: Susanne
authors.initials: S
authors.lastname: Liese
authors.forename: Christian
authors.initials: C
authors.lastname: Kuehne
authors.forename: Kai
authors.initials: K
authors.lastname: Ludwig
authors.forename: Jens
authors.initials: J
authors.lastname: Dernedde
authors.forename: Christoph
authors.initials: C
authors.lastname: Böttcher
authors.forename: Roland R
authors.initials: RR
authors.lastname: Netz
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008024:Ligands
chemical_list: D000998:Antiviral Agents; D008024:Ligands