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.

Autor:	Hampton JT; Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States., Lalonde TJ; Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States., Tharp JM; Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States., Kurra Y; Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States., Alugubelli YR; Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States., Roundy CM; Department of Entomology, Texas A&M University, College Station, Texas 77843, United States., Hamer GL; Department of Entomology, Texas A&M University, College Station, Texas 77843, United States., Xu S; Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States., Liu WR; Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.; Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, Texas 77030, United States.; Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, Texas 77843, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2022 Oct 21; Vol. 17 (10), pp. 2911-2922. Date of Electronic Publication: 2022 Sep 29.
DOI:	10.1021/acschembio.2c00565
Abstrakt:	Using 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 novel severe acute respiratory syndrome virus 2 (SARS-CoV-2) Spike protein, macrocyclic peptides that strongly inhibit the interaction between the Spike RBD and angiotensin-converting enzyme 2 (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 EC 50 value of 3.1 μM. The AlphaLISA-detected IC 50 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.
Databáze:	MEDLINE
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