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”. ► Second histidine (H) of EGFR-binding peptide was replaced arginine (R). ► EGFR(2R)-lytic had higher cytotoxic activity than that of original EGFR-lytic peptide. ► It produces higher binding ability to EGFR and improved anticancer activ...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2011-04, Vol.407 (2), p.383-388
Main Authors: Tada, Noriko, Horibe, Tomohisa, Haramoto, Mari, Ohara, Koji, Kohno, Masayuki, Kawakami, Koji
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - therapeutic use
Arginine - chemistry
Arginine - genetics
Breast Neoplasms - drug therapy
Cell Line, Tumor
Drug delivery
Drug resistance
EGFR
Female
Histidine - chemistry
Histidine - genetics
Humans
Hybrid peptide
Mice
Mice, Nude
Molecular targeting
Mutation
Peptides - chemistry
Peptides - genetics
Peptides - therapeutic use
Receptor, Epidermal Growth Factor - chemistry
Receptor, Epidermal Growth Factor - genetics
Receptor, Epidermal Growth Factor - therapeutic use
Recombinant Fusion Proteins - chemistry
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - therapeutic use
Xenograft Model Antitumor Assays
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Summary:► We previously reported that novel targeted “hybrid peptide”. ► Second histidine (H) of EGFR-binding peptide was replaced arginine (R). ► EGFR(2R)-lytic had higher cytotoxic activity than that of original EGFR-lytic peptide. ► It produces higher binding ability to EGFR and 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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2011.03.030