A peptide array pipeline for the development of Spike-ACE2 interaction inhibitors.

Autor: Chopra A; Institute of Biochemistry, Carleton University, Ottawa, ON, Canada; Department of Biology, Carleton University, Ottawa, ON, Canada., Shukri AH; Institute of Biochemistry, Carleton University, Ottawa, ON, Canada; Department of Biology, Carleton University, Ottawa, ON, Canada., Adhikary H; Institute of Biochemistry, Carleton University, Ottawa, ON, Canada; Department of Biology, Carleton University, Ottawa, ON, Canada., Lukinović V; Institute of Biochemistry, Carleton University, Ottawa, ON, Canada; Department of Biology, Carleton University, Ottawa, ON, Canada., Hoekstra M; Institute of Biochemistry, Carleton University, Ottawa, ON, Canada; Department of Biology, Carleton University, Ottawa, ON, Canada., Cowpland M; NuvoBio Corporation, 150 Isabella Street, Suite 150, Ottawa, ON, K1S 1V7, Canada., Biggar KK; Institute of Biochemistry, Carleton University, Ottawa, ON, Canada; Department of Biology, Carleton University, Ottawa, ON, Canada. Electronic address: Kyle.biggar@carleton.ca.
Jazyk: angličtina
Zdroj: Peptides [Peptides] 2022 Dec; Vol. 158, pp. 170898. Date of Electronic Publication: 2022 Oct 21.
DOI: 10.1016/j.peptides.2022.170898
Abstrakt: In humans, coronaviruses are the cause of endemic illness and have been the causative agents of more severe epidemics. Most recently, SARS-CoV-2 was the causative agent of the COVID19 pandemic. Thus, there is a high interest in developing therapeutic agents targeting various stages of the coronavirus viral life cycle to disrupt viral propagation. Besides the development of small-molecule therapeutics that target viral proteases, there is also interest molecular tools to inhibit the initial event of viral attachment of the SARS-CoV-2 Spike protein to host ACE2 surface receptor. Here, we leveraged known structural information and peptide arrays to develop an in vitro peptide inhibitor of the Spike-ACE2 interaction. First, from previous co-crystal structures of the Spike-ACE2 complex, we identified an initial 24-residue long region (sequence: STIEEQAKTFLDKFNHEAEDLFYQ) on the ACE2 sequence that encompasses most of the known contact residues. Next, we scanned this 24-mer window along the ACE2 N-terminal helix and found that maximal binding to the SARS-CoV-2 receptor binding domain (CoV2-RBD) was increased when this window was shifted nine residues in the N-terminal direction. Further, by systematic permutation of this shifted ACE2-derived peptide we identified mutations to the wildtype sequence that confer increased binding of the CoV2-RBD. Among these peptides, we identified binding peptide 19 (referred to as BP19; sequence: SLVAVTAAQSTIEEQAKTFLDKFI) as an in vitro inhibitor of the Spike-ACE2 interaction with an IC 50 of 2.08 ± 0.38 μM. Overall, BP19 adds to the arsenal of Spike-ACE2 inhibitors, and this study highlights the utility of systematic peptide arrays as a platform for the development of coronavirus protein inhibitors.
Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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