Peptide inhibitors of the interaction of the SARS-CoV-2 receptor-binding domain with the ACE2 cell receptor

   
Bibilashvili R.Sh.1, Sidorova M.V.1 , Dudkina U.S.1, Palkeeva M.E.1, Molokoedov A.S.1, Kozlovskaya L.I.2, Egorov A.M.3, Ishmukhametov A.A.2, Parfyonova Ye.V.1

1. National Medical Research Center for Cardiology, Moscow, Russia
2. Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products of the Russian Academy of Sciences, Moscow, Russia; Sechenov Moscow State Medical University, Moscow, Russia
3. Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products of the Russian Academy of Sciences, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia
Section: Experimental Study
DOI: 10.18097/PBMC20216703244      PubMed Id: 34142531
Year: 2021  Volume: 67  Issue: 3  Pages: 244-250
Computer simulation has been used to identify peptides that mimic the natural target of the SARS-CoV-2 coronavirus spike (S) protein, the angiotensin converting enzyme type 2 (ACE2) cell receptor. Based on the structure of the complex of the protein S receptor-binding domain (RBD) and ACE2, the design of chimeric molecules consisting of two 22-23-mer peptides linked to each other by disulfide bonds was carried out. The chimeric molecule X1 was a disulfide dimer, in which edge cysteine residues in the precursor molecules h1 and h2 were connected by the S-S bond. In the chimeric molecule X2, the disulfide bond was located in the middle of the molecule of each of the precursor peptides. The precursors h1 and h2 modelled amino acid sequences of α1- and α2-helices of the extracellular peptidase domain of ACE2, respectively, keeping intact most of the amino acid residues involved in the interaction with RBD. The aim of the work was to evaluate the binding efficiency of chimeric molecules and their RBD-peptides (particularly in dependence of the middle and edge methods of fixing the initial peptides h1 and h2). The proposed polypeptides and chimeric molecules were synthesized by chemical methods, purified (to 95-97% purity), and characterized by HPLC and MALDI-TOF mass spectrometry. The binding of the peptides to the SARS-CoV-2 RBD was evaluated by microthermophoresis with recombinant domains corresponding in sequence to the original Chinese (GenBank ID NC_045512.2) and the British (B. 1.1.7, GISAID EPI_ISL_683466) variants. Binding to the original RBD of the Chinese variant was detected in three synthesized peptides: linear h2 and both chimeric variants. Chimeric peptides were also bound to the RBD of the British variant with micromolar constants. The antiviral activity of the proposed peptides in Vero cell culture was also evaluated.
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Keywords: SARS-CoV-2, RBD, ACE2, peptide inhibitors, computer simulation
Citation:

Bibilashvili, R. Sh., Sidorova, M. V., Dudkina, U. S., Palkeeva, M. E., Molokoedov, A. S., Kozlovskaya, L. I., Egorov, A. M., Ishmukhametov, A. A., Parfyonova, Ye. V. (2021). Peptide inhibitors of the interaction of the SARS-CoV-2 receptor-binding domain with the ACE2 cell receptor. Biomeditsinskaya khimiya, 67(3), 244-250.
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