Synthetic α‐Helical Peptides as Potential Inhibitors of the ACE2 SARS‐CoV‐2 Interaction. (14th July 2022)

• Record Type: Journal Article
• Authors: Engelhardt, Pascal M.; Florez‐Rueda, Sebastián; Drexelius, Marco; Neudörfl, Jörg‐Martin; Lauster, Daniel; Hackenberger, Christian P. R.; Kühne, Ronald; Neundorf, Ines; Schmalz, Hans‐Günther
• Is Part Of: Chembiochem. Volume 23:Number 17(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-14
• Subjects: CD spectroscopy -- peptides -- protein-protein interactions -- SARS-CoV-2 -- secondary structures; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202200372
• Languages: English
• ISSNs: 1439-4227

Abstract

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). Abstract : The N ‐cap makes the difference : Aiming at the development of potential COVID‐19 drugs distorting the interaction between the SARS‐CoV‐2 spike protein and human ACE2, a series of N ‐capped peptides derived from the α1‐helix of ACE2 were prepared to increase the α‐helical content. This led to the discovery of a comparably short peptide binding to the spike protein with high affinity (KD =62 nM).