ACE2-derived peptides with enhanced efficacy for inhibition of SARS-COV-2 infection

Abstract

The coronavirus disease (COVID-19) originated the current world-wide pandemic situation. This disease is caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and the structural and biochemical basis of the infection mechanism has been widely investigated showing that the receptor binding domain (RBD) of the virus surface spike protein interacts with the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2). [1-3] Crystallographic studies of the RBD of SARS-CoV-2 with the full-length human ACE2 receptor exposed the amino acid residues that play a key role at the contact interface of the two proteins. [3,4] Most of the interactions between RBD and ACE2 receptor reside on the helix 1 of ACE2. It has been reported that the ¿-helix secondary structure is essential to obtain antiviral activity against the SARS-CoV-2 pseudovirus. [5] Several strategies have been published to increase the helicity content of the helix 1 peptide of ACE2. Curreli et al. designed four stapled peptides [5] while Karoyan et al. substituted the non-essential positions of the native helix 1 of ACE2 by amino acid residues such as Ala and/or Leu that display a higher helical folding propensity. [1] Both strategies showed an increase in the helical content and a potent SARS-CoV-2 inhibitory activity. Here, we report the development of a long-range macrocycle ACE2 derived peptides with the aim to stabilise the helical structure of the peptides and consequently, increase the potential ability to block SARS-CoV-2 attachment to the host cell. Chemical modifications of the peptides that show greater affinity against RBD will be conducted to obtain irreversible versions of the peptides. These modified peptides should be chemically stable and maintain the binding properties. Nonetheless, crosslinking between both components is expected due to the chemical reaction of the modified peptide with amino acid residues of the RBD that have a nucleophilic character. Finally, multivalent platforms will be synthesized following methodologies well established in our laboratory with the peptide candidates that show better results.

References [1] P. Karoyan, V. Vieillard, E. Odile, et al. Eur. bioRxiv. 2020, 1-17. [2] J. Shang, G. Ye, K. Shi, et al. Nature. 2020, 581, 221-224. [3] R. Yan, Y. Zhang, Y. Li, et al. Science. 2020, 367, 1444-1448. [4] D. Wrapp, N. Wang, K. Corbett, et al. Science. 2020, 367, 1260-1263. [5] F. Curreli, S. Victor, X. Tong, et al. MBio. 2020, 11, 1-13.