Improvement of native structure-based peptides as efficient inhibitors of protein-protein interactions of SARS-CoV-2 spike protein and human ACE2

Norbert Odolczyk; Joanna Klim; Małgorzata Podsiadła-Białoskórska; Maria Winiewska-Szajewska; Ewa Szolajska; Urszula Zielenkiewicz; Jarosław Poznański; Piotr Zielenkiewicz

doi:10.3389/fmolb.2022.983014

Improvement of native structure-based peptides as efficient inhibitors of protein-protein interactions of SARS-CoV-2 spike protein and human ACE2

Front Mol Biosci. 2022 Sep 28:9:983014. doi: 10.3389/fmolb.2022.983014. eCollection 2022.

Authors

Norbert Odolczyk^{1

2}, Joanna Klim¹, Małgorzata Podsiadła-Białoskórska¹, Maria Winiewska-Szajewska¹, Ewa Szolajska¹, Urszula Zielenkiewicz¹, Jarosław Poznański¹, Piotr Zielenkiewicz^{1

2}

Affiliations

¹ Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland.
² Laboratory of Systems Biology, Institute of Experimental Plant Biology and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland.

Abstract

New pathogens responsible for novel human disease outbreaks in the last two decades are mainly the respiratory system viruses. Not different was the last pandemic episode, caused by infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One of the extensively explored targets, in the recent scientific literature, as a possible way for rapid development of COVID-19 specific drug(s) is the interaction between the receptor-binding domain of the virus' spike (S) glycoprotein and human receptor angiotensin-converting enzyme 2 (hACE2). This protein-protein recognition process is involved in the early stages of the SARS-CoV-2 life cycle leading to the host cell membrane penetration. Thus, disrupting this interaction may block or significantly reduce the infection caused by the novel pathogen. Previously we have designed (by in silico structure-based analysis) three very short peptides having sequences inspirited by hACE2 native fragments, which effectively bind to the SARS-CoV-2 S protein and block its interaction with the human receptor. In continuation of the above mentioned studies, here we presented an application of molecular modeling approach resulting in improved binding affinity of the previously proposed ligand and its enhanced ability to inhibit meaningful host-virus protein-protein interaction. The new optimized hexapeptide binds to the virus protein with affinity one magnitude higher than the initial ligand and, as a very short peptide, has also great potential for further drug development. The peptide-based strategy is rapid and cost-effective for developing and optimizing efficient protein-protein interactions disruptors and may be successfully applied to discover antiviral candidates against other future emerging human viral infections.

Keywords: ACE2; COVID-19; SARS-CoV-2; angiotensin-converting enzyme-2; coronavirus; drug design; inhibitors of protein-protein interactions; peptides.