Premium
Peptide ligands for targeting the extracellular domain of EGFR: Comparison between linear and cyclic peptides
Author(s) -
Williams Tyrslai M.,
Sable Rushikesh,
Singh Sitanshu,
Vicente Maria Graca H.,
Jois Seetharama D.
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13125
Subject(s) - cyclic peptide , peptide , chemistry , target peptide , lysine , amino acid , biochemistry , combinatorial chemistry
Colorectal cancer (CRC) is the third most common solid internal malignancy among cancers. Early detection of cancer is key to increasing the survival rate of colorectal cancer patients. Overexpression of the EGFR protein is associated with CRC. We have designed a series of peptides that are highly specific for the extracellular domain of EGFR, based on our earlier studies on linear peptides. The previously reported linear peptide LARLLT, known to bind to EGFR, was modified with the goals of increasing its stability and its specificity toward EGFR. Peptide modifications, including D‐amino acid substitution, cyclization, and chain reversal, were investigated. In addition, to facilitate labeling of the peptide with a fluorescent dye, an additional lysine residue was introduced onto the linear (KLARLLT) and cyclic peptides cyclo(KLARLLT) ( Cyclo.L1 ). The lysine residue was also converted into an azide group in both a linear and reversed cyclic peptide sequences cyclo(K(N3)larllt) ( Cyclo.L1.1 ) to allow for subsequent “click” conjugation. The cyclic peptides showed enhanced binding to EGFR by SPR. NMR and molecular modeling studies suggest that the peptides acquire a β‐turn structure in solution. In vitro stability studies in human serum show that the cyclic peptide is more stable than the linear peptide.