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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2005-2-7
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pubmed:abstractText |
To dissect the enzyme inhibitory properties of the immunosuppressive cyclic undecapeptide cyclosporin A (CsA) and gain access to monospecific, non-calcineurin-inhibiting CsA derivatives, [D-Ser8]CsA was subjected to modifications at the D-Ser side chain. Thus, we modified a CsA residue flanking the calcineurin (CaN) and cyclophilin 18 (Cyp18) binding domains of CsA instead of the residues of the CaN binding domain in order to develop a new specificity-determining site within the cyclic peptide. The [O-(NH2 (CH2)5NHC(O)CH2)-D-Ser8]CsA (derivative 9), with an amino group on a tether, exhibits CsA-like inhibition of the peptidyl prolyl cis/trans isomerase activity of Cyp18 with an IC50 value of 3.2 nm, whereas the CaN inhibition by the Cyp18-derivative 9 complex is completely abolished. Consequently, this compound is not able to inhibit the proliferation and cytokine production of activated T cells. Structure-activity relationship studies with a series of [d-Ser(8)]CsA derivatives indicate that the positively charged side chain is an essential requirement for Cyp18-derivative 9 to be ineffective on CaN. Upon protecting the amino group in derivative 9 with the photolabile moiety 2-nitroveratryloxycarbonyl (NVOC), the Cyp18-[O-(NVOC-NH(CH2)5NHC(O)CH2)-D-Ser8]CsA (derivative 11) complex exhibits strong CaN inhibition and shows potent immunosuppressive activity. In stimulated T cells pretreated with derivative 11, a remarkable recovery of transcriptional activation of the nuclear factor of activated T cells (NFAT) has been achieved through light irradiation, as assessed with a NFAT reporter gene assay.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Calcineurin,
http://linkedlifedata.com/resource/pubmed/chemical/Carbon,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclophilins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclosporine,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione Transferase,
http://linkedlifedata.com/resource/pubmed/chemical/Immunosuppressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/NFATC Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
11
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pubmed:volume |
280
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4842-50
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:15572368-Calcineurin,
pubmed-meshheading:15572368-Carbon,
pubmed-meshheading:15572368-Cell Line,
pubmed-meshheading:15572368-Cell Proliferation,
pubmed-meshheading:15572368-Crystallography, X-Ray,
pubmed-meshheading:15572368-Cyclophilins,
pubmed-meshheading:15572368-Cyclosporine,
pubmed-meshheading:15572368-Cytokines,
pubmed-meshheading:15572368-DNA-Binding Proteins,
pubmed-meshheading:15572368-Dose-Response Relationship, Drug,
pubmed-meshheading:15572368-Genes, Reporter,
pubmed-meshheading:15572368-Glutathione Transferase,
pubmed-meshheading:15572368-Humans,
pubmed-meshheading:15572368-Immunosuppressive Agents,
pubmed-meshheading:15572368-Inhibitory Concentration 50,
pubmed-meshheading:15572368-Jurkat Cells,
pubmed-meshheading:15572368-Light,
pubmed-meshheading:15572368-Luciferases,
pubmed-meshheading:15572368-Models, Chemical,
pubmed-meshheading:15572368-Models, Molecular,
pubmed-meshheading:15572368-NFATC Transcription Factors,
pubmed-meshheading:15572368-Nuclear Proteins,
pubmed-meshheading:15572368-Peptides,
pubmed-meshheading:15572368-Protein Binding,
pubmed-meshheading:15572368-Protein Structure, Tertiary,
pubmed-meshheading:15572368-Serine,
pubmed-meshheading:15572368-T-Lymphocytes,
pubmed-meshheading:15572368-Time Factors,
pubmed-meshheading:15572368-Transcription Factors,
pubmed-meshheading:15572368-Transcriptional Activation
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pubmed:year |
2005
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pubmed:articleTitle |
Unexpected side chain effects at residue 8 of cyclosporin a derivatives allow photoswitching of immunosuppression.
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pubmed:affiliation |
Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120, Halle/Saale, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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