Synthesis and characterization of bispecific, antibody derived peptides as potential HIV-1 entry inhibitors
The aim of this project is to generate bispecific peptides with high binding affinity to the HIV-1 envelope glycoprotein (Env), as well as virus neutralization strength. These bispecific peptides will be designed to target two separate sites of HIV-1 Env, which 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.
Peptides derived from the CDRs of HIV-1 neutralizing antibodies (Haußner et al, 2017) might have improved characteristics in comparison to the antibodies themselves. Because of their smaller size, the peptides can get easier access to sterically shielded epitopes and penetrate tissue better.
The peptides will be rationally designed (in collaboration with Prof. Stich, Project C2) based on the 3D structures of the antibody-protein complexes (Deubler et al., 2023), and synthesized via solid-phase peptide synthesis (SPPS), which enables the introduction of nonproteinogenic amino acids, as well as other chemical modifications to enhance binding affinity and neutralization activity.
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References:
- Haußner et al. (2017) Synthetic antibody mimics for the inhibition of protein - ligand interactions. Curr Opin Chem Biol 40, 72-77.
- Deubler, M. et al. (2023) Computational Characterization of the Binding Properties of the HIV1-Neutralizing Antibody PG16 and Design of PG16-Derived CDRH3 Peptides. https://www.preprints.org/manuscript/202305.0281/v1
