Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives.

Autor:	Klein VG; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States., Bray WM; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States., Wang HY; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, 94158, United States., Edmondson Q; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States., Schwochert J; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States., Ono S; Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa 227-0033, Japan., Naylor MR; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States., Turmon AC; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States., Faris JH; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States., Okada O; Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa 227-0033, Japan., Taunton J; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, 94158, United States., Lokey RS; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2021 Aug 20; Vol. 16 (8), pp. 1354-1364. Date of Electronic Publication: 2021 Jul 12.
DOI:	10.1021/acschembio.1c00094
Abstrakt:	Cordyheptapeptide A is a lipophilic cyclic peptide from the prized Cordyceps fungal genus that shows potent cytotoxicity in multiple cancer cell lines. To better understand the bioactivity and physicochemical properties of cordyheptapeptide A with the ultimate goal of identifying its cellular target, we developed a solid-phase synthesis of this multiply N -methylated cyclic heptapeptide which enabled rapid access to both side chain- and backbone-modified derivatives. Removal of one of the backbone amide N -methyl (N-Me) groups maintained bioactivity, while membrane permeability was also preserved due to the formation of a new intramolecular hydrogen bond in a low dielectric solvent. Based on its cytotoxicity profile in the NCI-60 cell line panel, as well as its phenotype in a microscopy-based cytological assay, we hypothesized that cordyheptapeptide was acting on cells as a protein synthesis inhibitor. Further studies revealed the molecular target of cordyheptapeptide A to be the eukaryotic translation elongation factor 1A (eEF1A), a target shared by other lipophilic cyclic peptide natural products. This work offers a strategy to study and improve cyclic peptide natural products while highlighting the ability of these lipophilic compounds to effectively inhibit intracellular disease targets.
Databáze:	MEDLINE
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