tetano
Editor, Senior Moderator
Bioconjug Chem
. 2022 Jun 27.
doi: 10.1021/acs.bioconjchem.2c00166. Online ahead of print.
Design and Functional Analysis of Heterobifunctional Multivalent Phage Capsid Inhibitors Blocking the Entry of Influenza Virus
Lutz Adam[SUP] 1 2 [/SUP], Eva Müller[SUP] 3 [/SUP], Kai Ludwig[SUP] 4 [/SUP], Simon Klenk[SUP] 1 2 [/SUP], Daniel Lauster[SUP] 5 [/SUP], Susanne Liese[SUP] 6 7 [/SUP], Andreas Herrmann[SUP] 5 [/SUP], Christian P R Hackenberger[SUP] 1 2 [/SUP]
Affiliations
Abstract
Multiple conjugation of virus-binding ligands to multivalent carriers is a prominent strategy to construct highly affine virus binders for the inhibition of viral entry into host cells. In a previous study, we introduced rationally designed sialic acid conjugates of bacteriophages (Qβ) that match the triangular binding site geometry on hemagglutinin spike proteins of influenza A virions, resulting in effective infection inhibition in vitro and in vivo. In this work, we demonstrate that even partially sialylated Qβ conjugates retain the inhibitory effect despite reduced activity. These observations not only support the importance of trivalent binding events in preserving high affinity, as supported by computational modeling, but also allow us to construct heterobifunctional modalities. Capsids carrying two different sialic acid ligand-linker structures showed higher viral inhibition than their monofunctional counterparts. Furthermore, capsids carrying a fluorescent dye in addition to sialic acid ligands were used to track their interaction with cells. These findings support exploring broader applications as multivalent inhibitors in the future.
. 2022 Jun 27.
doi: 10.1021/acs.bioconjchem.2c00166. Online ahead of print.
Design and Functional Analysis of Heterobifunctional Multivalent Phage Capsid Inhibitors Blocking the Entry of Influenza Virus
Lutz Adam[SUP] 1 2 [/SUP], Eva Müller[SUP] 3 [/SUP], Kai Ludwig[SUP] 4 [/SUP], Simon Klenk[SUP] 1 2 [/SUP], Daniel Lauster[SUP] 5 [/SUP], Susanne Liese[SUP] 6 7 [/SUP], Andreas Herrmann[SUP] 5 [/SUP], Christian P R Hackenberger[SUP] 1 2 [/SUP]
Affiliations
- PMID: 35759354
- DOI: 10.1021/acs.bioconjchem.2c00166
Abstract
Multiple conjugation of virus-binding ligands to multivalent carriers is a prominent strategy to construct highly affine virus binders for the inhibition of viral entry into host cells. In a previous study, we introduced rationally designed sialic acid conjugates of bacteriophages (Qβ) that match the triangular binding site geometry on hemagglutinin spike proteins of influenza A virions, resulting in effective infection inhibition in vitro and in vivo. In this work, we demonstrate that even partially sialylated Qβ conjugates retain the inhibitory effect despite reduced activity. These observations not only support the importance of trivalent binding events in preserving high affinity, as supported by computational modeling, but also allow us to construct heterobifunctional modalities. Capsids carrying two different sialic acid ligand-linker structures showed higher viral inhibition than their monofunctional counterparts. Furthermore, capsids carrying a fluorescent dye in addition to sialic acid ligands were used to track their interaction with cells. These findings support exploring broader applications as multivalent inhibitors in the future.