Synthetic alpha-Helical Peptides as Potential Inhibitors of the ACE2 SARS-CoV-2 Interaction

During viral cell entry, the spike protein of SARS-CoV-2 binds to the alpha 1-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 alpha-helicity in short peptide sequences inspired by the ACE2 alpha 1-helix. Starting with Ac-QAKTFLDKFNHEAEDLFYQ-NH2 as a relevant section of alpha 1, a series of peptides, N-capped with either Ac-beta HAsp-[ProM-5] or Ac-beta HAsp-PP, were prepared and their alpha-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 alpha-helical content and, noteworthy, led to the identification of an Ac-beta HAsp-PP-capped peptide displaying a very strong binding affinity (K-D=62 nM)