Human respiratory syncytial virus (RSV) is the primary cause of acute lower
respiratory tract infections in children and the elderly worldwide, for which
neither a vaccine nor an effective therapy is approved. The entry of RSV into the
host cell is mediated by stepwise structural changes in the surface RSV fusion
(RSV-F) glycoprotein. Recent progress in structural and functional studies of
RSV-F glycoprotein revealed conformation-dependent neutralizing epitopes
which have become attractive targets for vaccine and therapeutic
development. As RSV-F is present on viral surface in a trimeric form, a
trivalent binding interaction between a candidate fusion inhibitor and the
respective epitopes on each of the three monomers is expected to prevent
viral infection at higher potency than a monovalent or bivalent inhibitor. Here
we demonstrate a novel RSV entry inhibitory approach by implementing a
trimeric DNA nanostructure as a template to display up to three linear peptide
moieties that simultaneously target an epitope on the surface of the prefusion
RSV-F protein. In order to design synthetic binding peptides that can be
coupled to the DNA nanostructure, the prefusion RSV-F-specific monoclonal
antibody (D25) was selected. Complementarity-determining region 3 (CDR3)
derived peptides underwent truncation and alanine-scanning mutagenesis
analysis, followed by systematic sequence modifications using non-canonical
amino acids. The most effective peptide candidate was used as a binding
moiety to functionalize the DNA nanostructure. The designed DNA-peptide
construct was able to block RSV infection on cells more efficiently than the
monomeric peptides, however a more moderate reduction of viral load was
observed in the lungs of infected mice upon intranasal application, likely due to
dissociation or absorption of the underlying DNA structure by cells in the lungs.Taken together, our results point towards the inhibitory potential of a novel
trimeric DNA-peptide based approach against RSV and open the possibility to
apply this platform to target other viral infections.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:90632 |
| Date | 21 March 2024 |
| Creators | Issmail, Leila, Möser, Christin, Jäger, Christian, Altattan, Basma, Ramsbeck, Daniel, Kleinschmidt, Martin, Buchholz, Mirko, Smith, David, Grunwald, Thomas |
| Publisher | Frontiers Media |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2673-818X, 10.3389/fviro.2022.994843 |
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