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Natural cyclic peptide and its analogs as carboxypeptidase A inhibitors

Monday, October 24, 2011 — Poster Session I

Noon – 2:00 p.m.

Natcher Conference Center




  • P Cheruku
  • A Plaza
  • JL Keffer
  • CA Bewley


Carboxypeptidase A(CPA) is a metalloprotease, which serves as a model in the development of inhibitor design strategies that can be translated to other metalloproteases of great medicinal importance. Anabaenopeptins, a family of uredo- peptides are known as potent CPA inhibitors at low nanomolar concentrations. We isolated and structure elucidated PLA3-6, an anabaenopeptin-like cyclic peptide from the marine sponge Theonella swinhoei, harboring a three-residue(L-Phe, L-Ile, D-Lys)13-membered lactam ring formed by cyclization between the C-terminal acid and the ε-amine of an N-terminal lysine residue. The fourth amino acid(L-Phe)is attached to the cyclic peptide via an exocyclic urea function linked to the α-amine of Lys. In order to unravel the structural parameters that determine their activities, a collection of PLA3-6 together with analogues with varied amino acid structures and stereochemistries were synthesized by a combined solution- and solid-phase approach. PLA3-6 showed the carboxypeptidase A inhibitory activity at mid-nanomolar concentration(IC50=250 nM). By changing the stereochemistry at Lys and exocyclic Phe caused the loss of activity, showing that the presence of D-Lys and L-Phe is important for the inhibitory activity. For the linear peptide analog the activity is diminished by 18-fold (IC50=4.5uM). All peptides synthesized were failed to inhibit carboxypeptidase U.

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