A single replacement of histidine to arginine in EGFR-lytic hybrid peptide demonstrates the improved anticancer activity.

We previously reported that novel targeted "hybrid peptide" in which epidermal growth factor receptor (EGFR) binding peptide was conjugated with lytic-type peptide had selective cytotoxic activity to EGFR expressing cancer cell lines, and in vivo analysis revealed that this EGFR-lytic peptide displayed significant antitumor activity in a xenograft model of human breast cancer which was resistant to tyrosine kinase inhibitor drugs. As an attempt to improve the selective anticancer activity of EGFR-lytic peptide, we modified the EGFR-binding peptide through introducing the mutation of amino acid according to biophysical analysis by biomolecular interaction and circular dichroism (CD) spectra. When cytotoxic activity of EGFR-lytic or EGFR(2R)-lytic hybrid peptides was investigated in various human cancer and normal cell lines, it was demonstrated that EGFR(2R)-lytic, in which second histidine (H) of EGFR-binding peptide was replaced to arginine (R) had 1.2-1.9-fold higher cytotoxic activity than that of original EGFR-lytic peptide. In vivo analysis also revealed that this modified peptide displayed significant antitumor activity at as low as 1 mg/kg dosage. These results suggest that mutated arginine on EGFR-lytic peptide produces higher binding ability to EGFR on cancer cells, and thereby the improved anticancer activity. Copyright © 2011 Elsevier Inc. All rights reserved.

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Noriko Tada, Tomohisa Horibe, Mari Haramoto, Koji Ohara, Masayuki Kohno, Koji Kawakami. A single replacement of histidine to arginine in EGFR-lytic hybrid peptide demonstrates the improved anticancer activity. Biochemical and biophysical research communications. 2011 Apr 8;407(2):383-8

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PMID: 21396910

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