Title
Synthetic α-Helical Peptides as Potential Inhibitors of the ACE2 SARS-CoV-2 Interaction
Author
Pascal M. Engelhardt, Sebastián Florez-Rueda, Marco Drexelius, Dr. Jörg-Martin Neudörfl, Dr. Daniel Lauster, Prof. Dr. Christian P. R. Hackenberger, Dr. Ronald Kühne, Prof. Dr. Ines Neundorf, Prof. Dr. Hans-Günther Schmalz
Year
2022
Journal
ChemBioChem
Abstract
During viral cell entry, the spike protein of SARS-CoV-2 binds to the α1-helix motif of human angiotensin-converting enzyme 2 (ACE2). Thus, alpha-helical peptides mimicking this motif may serve as inhibitors of viral cell entry. For this purpose, we employed the rigidified diproline-derived module ProM-5 to induce α-helicity in short peptide sequences inspired by the ACE2 α1-helix. Starting with Ac-QAKTFLDKFNHEAEDLFYQ-NH2 as a relevant section of α1, a series of peptides, N-capped with either Ac-βHAsp-[ProM-5] or Ac-βHAsp-PP, were prepared and their α-helicities were investigated. While ProM-5 clearly showed a pronounced effect, an even increased degree of helicity (up to 63 %) was observed in sequences in which non-binding amino acids were replaced by alanine. The binding affinities of the peptides towards the spike protein, as determined by means of microscale thermophoresis (MST), revealed only a subtle influence of the α-helical content and, noteworthy, led to the identification of an Ac-βHAsp-PP-capped peptide displaying a very strong binding affinity (KD=62 nM).
Instrument
J-715
Keywords
spike protein, ACE2, peptide, affinity, α-Helical, SARS-CoV-2, interaction