Bispecific antiviral peptides targeting SARS-CoV-2
The aim of this project is to implement the concept of bispecificity into the design and generation of antiviral peptides, which target separate, yet spatially proximate regions of viral proteins, such as the SARS-CoV-2 Spike protein. This will include bispecific peptides generated by fusion of our previously developed LW25.13 (Weißenborn et al., 2022), which targets the receptor binding domain (RBD) of the Spike protein, to peptides derived from the HR2 region of the Spike protein, which interfere with the fusion of the virus with the host cell (Lan et al., 2023). These peptides will be inter-connected by a chemical linker to generate bispecific ligands, whose protein binding and virus neutralizing properties will be assessed experimentally. Addressing two protein sites simultaneously by bispecific peptides may counteract the development of resistance. Furthermore, such bivalent interaction is expected to result in a synergistic effect, which is demonstrated by a higher antiviral activity of the heterodimeric peptides, compared to the individual peptide components.
All peptides will be generated through chemical synthesis, which enables the incorporation of non-proteinogenic amino acids and other chemical moieties, such as PEG-based linker amino acids, as well as conformational constraint through cyclisation. This will enable the fine-tuning of the correct spatial arrangement of the two functional components within the bispecific peptides. The virus neutralizing capacity of the generated peptides will be assessed in collaboration with projects C3 and C5.
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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)
- Lan, Q., et al. (2023). "Pan-coronavirus fusion inhibitors to combat COVID-19 and other emerging coronavirus infectious diseases." J Med Virol. 2023 Jan; 95(1)
