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An orally active reversible inhibitor of cathepsin S inhibits human trans vivo delayed-type hypersensitivity.

Abstract
Cathepsin S is a major histocompatibility complex (MHC) class II associated invariant chain (Ii) degrading enzyme expressed in antigen presenting cells such as B cells and dendritic cells. This enzyme is essential for MHC class II associated antigen processing and presentation to CD4(+) T cells. Compound I, a selective, reversible and orally bioavailable, inhibitor of cathepsin S, with molecular IC(50)=9 nM, has been recently described. We have tested the effects of compound I in a trans vivo model of delayed-type hypersensitivity. Human peripheral blood mononuclear cells (7-10 x 10(6)) from tetanus-sensitized donors were co-injected with tetanus toxoid (0.25 Lf) into C57Bl/6 mouse footpads. At 24 h, significant footpad swelling (+0.024+/-0.001 cm) characterized by an influx of mouse neutrophils and monocytes was observed. Injection of peripheral blood mononuclear cells alone caused negligible swelling (0.002+/-0.0002 cm). Anti-human MHC class II (HLA-DR, DP, DQ) antibody (5 mg/kg, i.p.) inhibited the swelling 91+/-7%, thus demonstrating a role of human antigen presenting cells in this model. Compound I (10, 30, and 100 mg/kg, p.o.) inhibited the response with an ED50 of approximately 18 mg/kg. Compound III, a less active analogue (molecular IC50>20 microM) had no effect. Furthermore, pretreatment of peripheral blood mononuclear cells with 10 nM compound II, an irreversible inhibitor (molecular IC50=11 nM) inhibited swelling 87+/-4%. These findings support the role of cathepsin S in human delayed-type hypersensitivity. Inhibition of cathepsin S with compound I may be useful in the treatment of human autoimmune diseases like rheumatoid arthritis and multiple sclerosis.
AuthorsSudha N Desai, Della M White, Kathryn M O'shea, Maryanne L Brown, Charles L Cywin, Denice M Spero, Maret J Panzenbeck
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 538 Issue 1-3 Pg. 168-74 (May 24 2006) ISSN: 0014-2999 [Print] Netherlands
PMID16631730 (Publication Type: Journal Article)
Chemical References
  • Enzyme Inhibitors
  • Cathepsins
  • cathepsin S
Topics
  • Administration, Oral
  • Animals
  • Biological Availability
  • Cathepsins (antagonists & inhibitors, genetics)
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (chemistry, pharmacokinetics, pharmacology)
  • Hypersensitivity, Delayed (immunology, pathology, prevention & control)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Structure
  • Structure-Activity Relationship

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