Structure and Activity of CPNGRC: A Modified CD13/APN Peptidic Homing Motif

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 su...

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Bibliographic Details
Published in:Chemical biology & drug design 2010-06, Vol.75 (6), p.551-562
Main Authors: 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
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Amino Acid Sequence
aminopeptidase
Apoptosis
CD13 Antigens - antagonists & inhibitors
CD13 Antigens - metabolism
Kinetics
ligand
Ligands
Magnetic Resonance Spectroscopy
NMR
peptide
Peptides - chemistry
Peptides - pharmacology
tumor
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Summary: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 IC₅₀ 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.
ISSN:1747-0277
1747-0285
DOI:10.1111/j.1747-0285.2010.00974.x