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Research Project: Enhanced Cotton for Value-Added Applications

Location: Cotton Chemistry and Utilization Research

Title: Structure/function analysis of truncated amino-terminal ACE2 peptide analogs that bind SARS-CoV-2 spike glycoprotein

item Mackin, Robert
item Edwards, Judson - Vince
item ATUK, E. BERK - Tulane University
item BELTRAMI, NOAH - Tulane University
item Condon, Brian
item French, Alfred - Al

Submitted to: Molecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/21/2022
Publication Date: 3/23/2022
Citation: Mackin, R.T., Edwards, J.V., Atuk, E.B., Beltrami, N., Condon, B.D., Jayawickramarajah, J., French, A.D. 2022. Structure/function analysis of truncated amino-terminal ACE2 peptide analogs that bind SARS-CoV-2 spike glycoprotein. Molecules. 27:2070.

Interpretive Summary: The COVID-19 pandemic has burdened the entire world, and due to the high transmission rate, the virus continues to spread. To help address this issue, we have developed a series of synthetic peptides to bind to the SARS-CoV-2 virus, allowing for capture and detection of the pathogen. The results from our study show ten peptides bind to the virus with the strongest producing micromolar binding affinity. We assess how various features of these peptides affect the binding strength and suggest ways of improving these molecules in future studies. By further optimizing the peptides, we can potentially develop viral inhibitors for COVID-19 positive patients or attach the peptides to textile surfaces and produce wearable items which actively capture the virus and prevent infection.

Technical Abstract: The burden of the SARS-CoV-2 pandemic is thought to result from a high viral transmission rate. Therefore, numerous avenues to viral inhibition and detection for abrogation have been examined. Here we consider mechanisms that influence host-cell virus binding between the SARS-CoV-2 spike glycoprotein (SPG) and the human angiotensin converting enzyme 2 (ACE2) with a series of peptides designed to mimic a portion of ACE2. The peptides were designed for propensity to adopt a helical conformation analogous to the N-terminal a helix of ACE2 and experimentally shown to bind to a recombinant SPG receptor binding domain (RBD) through surface plasmon resonance measurements. The approach examines putative structure/function motifs for their SPG-determined binding affinity based on correspondence of primary sequence modifications in the ACE2 peptide analogs and secondary structural changes as judged by circular dichroism. Subsequently, a cyclic peptide (c[KFNHEAEDLFEKLM]) was characterized in an a helical conformation with micromolar affinity (kd = 500 µM). Thus, stabilizing the helical structure through cyclization improves the binding constant by an order of magnitude compared to identical linear primary sequences. This structure/function approach, employing minimal sequence design, is contrasted with previously reported ones employing larger peptides. Also, an influence of end-group peptide analog modifications and residue substitution indicated net peptide charge as a property that mediates SPG binding. Therefore, we survey the relevance of reported virus variant SPG RBD charge alterations, and further support the hypothesis that charge is important in mediating enhanced viral fusion as a factor in host cell-virus variant interaction, presenting the perspective use of charge in design of virus-binding surfaces to facilitate uptake. Overall, these findings should be useful considerations in future analog design.