title: High-affinity cyclic peptide matriptase inhibitors.
abstract: BACKGROUND
  Sunflower trypsin inhibitor-1 (SFTI-1) and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) are potent protease inhibitors comprising a cyclic backbone.
  
  
  RESULTS
  Elucidation of structure-activity relationships for SFTI-1 and MCoTI-II was used to design inhibitors with enhanced inhibitory activity.
  
  
  CONCLUSIONS
  An analog of MCoTI-II is one of the most potent inhibitors of matriptase.
  
  
  CONCLUSIONS
  These results provide a solid basis for the design of selective peptide inhibitors of matriptase with therapeutic potential. The type II transmembrane serine protease matriptase is a key activator of multiple signaling pathways associated with cell proliferation and modification of the extracellular matrix. Deregulated matriptase activity correlates with a number of diseases, including cancer and hence highly selective matriptase inhibitors may have therapeutic potential. The plant-derived cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), is a promising drug scaffold with potent matriptase inhibitory activity. In the current study we have analyzed the structure-activity relationships of SFTI-1 and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II), a structurally divergent trypsin inhibitor from Momordica cochinchinensis that also contains a cyclic backbone. We show that MCoTI-II is a significantly more potent matriptase inhibitor than SFTI-1 and that all alanine mutants of both peptides, generated using positional scanning mutagenesis, have decreased trypsin affinity, whereas several mutations either maintain or result in enhanced matriptase inhibitory activity. These intriguing results were used to design one of the most potent matriptase inhibitors known to date with a 290 pm equilibrium dissociation constant, and provide the first indication on how to modulate affinity for matriptase over trypsin in cyclic peptides. This information might be useful for the design of more selective and therapeutically relevant inhibitors of matriptase.
authors.affiliation: La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Pedro
authors.initials: P
authors.lastname: Quimbar
authors.forename: Uru
authors.initials: U
authors.lastname: Malik
authors.forename: Christian P
authors.initials: CP
authors.lastname: Sommerhoff
authors.forename: Quentin
authors.initials: Q
authors.lastname: Kaas
authors.forename: Lai Y
authors.initials: LY
authors.lastname: Chan
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Huang
authors.forename: Maresa
authors.initials: M
authors.lastname: Grundhuber
authors.forename: Kerry
authors.initials: K
authors.lastname: Dunse
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Anderson
authors.forename: Norelle L
authors.initials: NL
authors.lastname: Daly
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020134:Catalytic Domain; D006368:Helianthus / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D029775:Momordica / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D010940:Plant Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D010456:Peptides, Cyclic; D010940:Plant Proteins; C448501:SFTI-1 peptide, sunflower; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C485596:ST14 protein, human
keywords: Molecular Modeling; Nuclear Magnetic Resonance; Peptide Conformation; Peptides; Protease Inhibitor
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