Premium
Structure and Activity of CPNGRC: A Modified CD13/APN Peptidic Homing Motif
Author(s) -
Plesniak Leigh A.,
Salzameda Bridget,
Hinderberger Holly,
Regan Elizabeth,
Kahn James,
Mills Stephen A.,
Teriete Peter,
Yao Yong,
Jennings Patricia,
Marassi Francesca,
Adams Joseph A.
Publication year - 2010
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/j.1747-0285.2010.00974.x
Subject(s) - peptide , aminopeptidase , docking (animal) , peptide sequence , peptidomimetic , biochemistry , chemistry , oligopeptide , stereochemistry , biophysics , biology , amino acid , leucine , gene , medicine , nursing
Asn‐Gly‐Arg peptides have been designed as vehicles for the delivery of chemotherapeutics, magnetic resonance imaging contrast agents, and fluorescence labels to tumor cells, and cardiac angiogenic tissue. Specificity is derived via an interaction with aminopeptidase N, also known as CD13, a cell surface receptor that is highly expressed in angiogenic tissue. Peptides containing the CNGRC homing sequence tethered to a pro‐apoptotic peptide sequence have the ability to specifically induce apoptosis in tumor cells. We have now identified a modification to the Asn‐Gly‐Arg homing sequence motif that improves overall binding affinity to aminopeptidase N. Through the addition of a proline residue, the new peptide with sequence, CPNGRC, inhibits aminopeptidase N proteolytic activity with an IC 50 of 10 μ m , a value that is 30‐fold lower than that for CNGRC. Both peptides are cyclized via a disulfide bridge between cysteines. Steady‐state kinetic experiments suggest that efficient aminopeptidase N inhibition is achieved through the highly cooperative binding of two molecules of CPNGRC. We have used NMR‐derived structural constraints for the elucidation of the solution structures CNGRC and CPNGRC. Resulting structures of CNGRC and CPNGRC have significant differences in the backbone torsion angles, which may contribute to the enhanced binding affinity and demonstrated enzyme inhibition by CPNGRC.