Isoform-specific inhibition of cyclophilins.
Cyclophilins belong to the enzyme class of peptidyl prolyl cis-trans isomerases which catalyze the cis-trans isomerization of prolyl bonds in peptides and proteins in different folding states. Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4(+) T cells by the inhibitor provided biological proof of discrimination in vivo.
Daum
Sebastian
S
Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, 06120 Halle/Saale, Germany.
Schumann
Michael
M
Mathea
Sebastian
S
Aumüller
Tobias
T
Balsley
Molly A
MA
Constant
Stephanie L
SL
de Lacroix
Boris Féaux
BF
Kruska
Fabian
F
Braun
Manfred
M
Schiene-Fischer
Cordelia
C
D000818:Animals; D001572:Benzofurans / Q000737:chemistry; D001667:Binding, Competitive; D055162:Biocatalysis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D020134:Catalytic Domain; D002633:Chemotaxis / Q000187:drug effects; D021984:Cyclophilin A / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005454:Fluorescence Polarization; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011485:Protein Binding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
D001572:Benzofurans; D004791:Enzyme Inhibitors; D007189:Indans; D007527:Isoenzymes; D011994:Recombinant Proteins; C081786:cyclophilin B; D016572:Cyclosporine; D021984:Cyclophilin A; D021983:Cyclophilins