The search for potential COVID-19 drugs is an important, yet challenging task. A promising concept is the inhibition of viral cell entry using synthetic molecules that inhibit the interaction between the spike protein of SARS-CoV-2 and its “docking station” on the surface of human cells, the receptor angiotensin-converting enzyme 2 (ACE2, binding region pictured).
Ines Neundorf, Hans-Günther Schmalz, University of Cologne, Germany, and colleagues have studied a series of peptides that could inhibit this interaction. The studied peptides were prepared using solid phase peptide synthesis. The team discovered a comparably short peptide, consisting of only 24 amino acid residues, that binds to the viral spike protein with excellent affinity (in the nanomolar range).
To mimic the structure of the α1-helix of ACE2, which plays a key role in the interaction with the spike protein (pictured), the researchers initially used a rigidified diprolin unit called ProM-5 as an N-cap (the amino acids at the N terminus of the helix). This was meant to induce the required α-helix conformation in the attached peptide chain. Surprisingly, however, a peptide with a simple diprolin-based N-cap (originally synthesized only as a control) showed even better binding to ACE2.
Based on these results, the researchers concluded that α-helical preorganization only partly determines the binding affinity. The work may contribute to the future development of peptide-based drugs addressing α-helix-binding protein domains.
- Synthetic α‐Helical Peptides as Potential Inhibitors of the ACE2 SARS‐CoV‐2 Interaction,
Pascal M. Engelhardt, Sebastián Florez Rueda, Marco Drexelius, Jörg-Martin Neudörfl, Daniel Lauster, Christian P. R. Hackenberger, Ronald Kühne, Ines Neundorf, Hans-Günther Schmalz,
ChemBioChem 2022.
https://doi.org/10.1002/cbic.202200372
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- Collection: SARS-CoV-2 Virus
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