Linked Life Data

7473543

Source:http://linkedlifedata.com/resource/pubmed/id/7473543

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
21
pubmed:dateCreated
1995-11-28
pubmed:abstractText
Four analogs of cyclosporin A (CsA) were synthesized to determine if the biological activities of CsA analogs generated by multiple amino acid replacements are predictable from the effects on biological activity of analogs with single residue changes. CsA analogs [Phe7]CsA (8a), [D-MeAla3,Phe7]CsA (8b), [D-Ser8,Phe7]CsA (8c), and [D-MeAla3,Phe7,D-Ser8]CsA (8d) were designed by modification of positions 3, 7, and 8, which are adjacent to one effector region of the cyclophilin-bound CsA complex. The syntheses of CsA analogs 8a-d were carried out by suitable modifications of the reported strategy. Each analog was characterized by NMR in deuterated chloroform and DMSO solutions, and their biological activities as inhibitors of cis-trans-peptidyl prolyl isomerase (PPIase), inhibitors of proliferation in BDF1 mouse spleen cells stimulated with concanavalin A (Con A), and inhibitors of IL-2 release stimulated with PMA/ionomycin by Jurkat cells were determined. Incorporation of the phenylalanine residue in position 7 diminished activities 5-8-fold. Substitution at position 3 decreased activity nearly 2-fold, and substitution at position 8 did not lower activities. However, when all three modifications (D-MeAla3,Phe7, and D-Ser8) were incorporated into one molecule, the resulting analog, 8d, was found to bind more tightly to cyclophilin than CsA (Ki = 3 +/- 1.5 vs 6 +/- 2 nM) and to produce the full immunosuppressive effect in the other assay systems. Our structure-activity results show that combinations of substitutions that individually lower PPIase or immunosuppressive activity produce fully active analogs when combined in a single compound. These results suggest that other, multimodified CsA derivatives may be discovered that possess excellent or improved immunosuppressive activities even though they contain a substitution that otherwise reduces immunosuppressive activity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
38
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4164-70
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:7473543-Acrylic Resins, pubmed-meshheading:7473543-Amino Acid Isomerases, pubmed-meshheading:7473543-Amino Acid Sequence, pubmed-meshheading:7473543-Animals, pubmed-meshheading:7473543-Carrier Proteins, pubmed-meshheading:7473543-Cell Division, pubmed-meshheading:7473543-Concanavalin A, pubmed-meshheading:7473543-Cyclosporins, pubmed-meshheading:7473543-Enzyme Inhibitors, pubmed-meshheading:7473543-Immunosuppressive Agents, pubmed-meshheading:7473543-Magnetic Resonance Spectroscopy, pubmed-meshheading:7473543-Mice, pubmed-meshheading:7473543-Molecular Sequence Data, pubmed-meshheading:7473543-Molecular Structure, pubmed-meshheading:7473543-Peptidylprolyl Isomerase, pubmed-meshheading:7473543-Spleen, pubmed-meshheading:7473543-Structure-Activity Relationship, pubmed-meshheading:7473543-Succinimides
pubmed:year
1995
pubmed:articleTitle
Cyclosporin analogs modified in the 3,7,8-positions: substituent effects on peptidylprolyl isomerase inhibition and immunosuppressive activity are nonadditive.
pubmed:affiliation
School of Pharmacy, University of Wisconsin-Madison 53706, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.