The first-in-class peptide binder to the SARS-CoV-2 spike protein

G. Zhang, S. Pomplun, A. R. Loftis, A. Loas, B. L. Pentelute

10.1101/2020.03.19.999318

Research curated

Abstract

Coronavirus disease 19 (COVID-19) is an emerging global health crisis. With over 200,000 confirmed cases to date, this pandemic continues to expand, spurring research to discover vaccines and therapies. SARS-CoV-2 is the novel coronavirus responsible for this disease. It initiates entry into human cells by binding to angiotensin-converting enzyme 2 (ACE2) via the receptor binding domain (RBD) of its spike protein (S). Disrupting the SARS-CoV-2-RBD binding to ACE2 with designer drugs has the potential to inhibit the virus from entering human cells, presenting a new modality for therapeutic intervention. Peptide-based binders are an attractive solution to inhibit the RBD-ACE2 interaction by adequately covering the extended protein contact interface. Using molecular dynamics simulations based on the recently solved ACE2 and SARS-CoV-2-RBD co-crystal structure, we observed that the ACE2 peptidase domain (PD) 1 helix is important for binding SARS-CoV-2-RBD. Using automated fast-flow peptide synthesis, we chemically synthesized a 23-mer peptide fragment of the ACE2 PD 1 helix composed entirely of proteinogenic amino acids. Chemical synthesis of this human derived sequence was complete in 1.5 hours and after work up and isolation >20 milligrams of pure material was obtained. Bio-layer interferometry revealed that this peptide specifically associates with the SARS-CoV-2-RBD with low nanomolar affinity. This peptide binder to SARS-CoV-2-RBD provides new avenues for COVID-19 treatment and diagnostic modalities by blocking the SARS-CoV-2 spike protein interaction with ACE2 and thus precluding virus entry into human cells.

Source: BioRxiv

Related molecules

Name	Synonyms	Genes
Spike glycoprotein	Spike protein, S glycoprotein, S-Protein, S1, S2, S3, Peplomer protein, E2	S, ORF2