Abstract
Calcineurin inhibitors such as cyclosporine A and FK506 are effective immunosuppressants but produce severe side effects. Rational modification of a previously reported peptide inhibitor, GPHPVIVITGPHEE (KD ∼ 500 nM), by replacing the two valine residues with tert-leucine and the C-terminal proline with a cis-proline analogue, gave an improved inhibitor ZIZIT-cisPro, which binds to calcineurin with a KD value of 2.6 nM and is more resistant to proteolysis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Amino Acid Sequence
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Amino Acid Substitution
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Binding Sites
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Calcineurin / metabolism*
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Calcineurin Inhibitors / blood
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Calcineurin Inhibitors / chemistry*
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Calcineurin Inhibitors / pharmacology*
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Drug Stability
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HeLa Cells
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Humans
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Models, Molecular
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NFATC Transcription Factors / metabolism*
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Peptides / blood
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Peptides / chemistry*
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Peptides / pharmacology*
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Protein Binding
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Protein Conformation
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Calcineurin Inhibitors
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NFATC Transcription Factors
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Peptides
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Calcineurin