Bispecific antiviral peptides targeting SARS-CoV-2
The aim of this project is to design bispecific peptides with high affinity to the SARS-CoV-2 Spike protein, as candidates for broadly neutralizing antiviral peptides. These peptides will target two different binding sites of the Spike protein, i.e. the N‑terminal domain (NTD) and the receptor binding domain (RBD), respectively. These two peptides will be covalently linked with a chemical linker. Such heterodimeric, bispecific peptides can be expected to exert synergistic effects that may enhance the neutralization breadth, overall antiviral activity and counteract viral resistances.
In our group RBD-binding peptides with a strong neutralizing activity against SARS-CoV-2 were generated in previous cohorts of this Research Training Group (Weißenborn et al. 2022).
Using structure-based computational strategies, the group of Prof. Sticht has developed a strategy to systematically predict promising NTD antibodies for the design of antibody-mimetic peptides. Based on these predictions, peptides will be designed, synthesized, and their interaction with the NTD will be assessed in binding and competition assays. Subsequently, peptides with confirmed NTD-binding activity will be covalently linked to one of our RBD-binding peptides. The resulting bispecific peptides will then be characterized with respect to their binding properties, inhibitory potential, and overall neutralization capacity.
All peptides will be generated through solid-phase peptide synthesis (SPPS). The chemical synthesis of peptides enables the inclusion of non-proteinogenic amino acids and the addition of chemical moieties, e.g. PEG-based linkers. Further chemical modifications such as a cyclization can stabilize peptides in their conformation and stabilize them against proteolytic degradation. The neutralization assays will be performed in collaboration with the group of Prof. Überla (C5).
References: Weißenborn, L., et al. (2022). "Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein." Int J Mol Sci 23(11). https://doi.org/10.3390/ijms23116309
