A Novel Regioselective Approach to Cyclize Phage-Displayed Peptides in Combination with Epitope-Directed Selection to Identify a Potent Neutralizing Macrocyclic Peptide for SARS-CoV-2

dc.contributor.authorHampton, J. Trae
dc.contributor.authorLalonde, Tyler J.
dc.contributor.authorTharp, Jeffery M.
dc.contributor.authorKurra, Yadagiri
dc.contributor.authorAlugubelli, Yugendar R.
dc.contributor.authorRoundy, Christopher M.
dc.contributor.authorHamer, Gabriel L.
dc.contributor.authorXu, Shiqing
dc.contributor.authorLiu, Wenshe Ray
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicine
dc.date.accessioned2024-09-12T08:07:49Z
dc.date.available2024-09-12T08:07:49Z
dc.date.issued2022
dc.description.abstractUsing the regioselective cyanobenzothiazole condensation reaction with an N-terminal cysteine and the chloroacetamide reaction with an internal cysteine, a phage-displayed macrocyclic 12-mer peptide library was constructed and subsequently validated. Using this library in combination with iterative selections against two epitopes from the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, macrocyclic peptides that strongly inhibit the interaction between the Spike RBD and ACE2, the human host receptor of SARS-CoV-2, were identified. The two epitopes were used instead of the Spike RBD to avoid selection of nonproductive macrocyclic peptides that bind RBD but do not directly inhibit its interactions with ACE2. Antiviral tests against SARS-CoV-2 showed that one macrocyclic peptide is highly potent against viral reproduction in Vero E6 cells with an EC50 value of 3.1 μM. The AlphaLISA-detected IC50 value for this macrocyclic peptide was 0.3 μM. The current study demonstrates that two kinetically-controlled reactions toward N-terminal and internal cysteines, respectively, are highly effective in the construction of phage-displayed macrocyclic peptides, and the selection based on the SARS-CoV-2 Spike epitopes is a promising methodology in the identification of peptidyl antivirals.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationHampton JT, Lalonde TJ, Tharp JM, et al. Novel Regioselective Approach to Cyclize Phage-Displayed Peptides in Combination with Epitope-Directed Selection to Identify a Potent Neutralizing Macrocyclic Peptide for SARS-CoV-2. ACS Chem Biol. 2022;17(10):2911-2922. doi:10.1021/acschembio.2c00565
dc.identifier.urihttps://hdl.handle.net/1805/43283
dc.language.isoen_US
dc.publisherAmerican Chemical Society
dc.relation.isversionof10.1021/acschembio.2c00565
dc.relation.journalACS Chemical Biology
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectPhage display
dc.subjectMacrocyclic peptides
dc.subjectAsymmetric cyclization
dc.subjectSARS-CoV-2
dc.subjectAntiviral
dc.titleA Novel Regioselective Approach to Cyclize Phage-Displayed Peptides in Combination with Epitope-Directed Selection to Identify a Potent Neutralizing Macrocyclic Peptide for SARS-CoV-2
dc.typeArticle
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