A study of the correlation between cyclophilin binding and in vitro immunosuppressive activity of cyclosporine A and analogues.
In order to establish whether CyP is the pharmacologically relevant CsA receptor, the CyP binding v immunosuppressive activity was measured for an extensive, structurally varied group of CsA analogues. Overall, CyP binding was found to parallel immunosuppressive activity. Other than MeAla6-CsA, the few exceptions to the correlation could be ascribed to cellular metabolism. These results strongly implicate CyP or a related protein in the mechanism of action of cyclosporine.
Durette
P L
PL
Department of Medicinal Chemistry, Immunology and Inflammation, Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065.
Boger
J
J
Dumont
F
F
Firestone
R
R
Frankshun
R A
RA
Koprak
S L
SL
Lin
C S
CS
Melino
M R
MR
Pessolano
A A
AA
Pisano
J
J
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003524:Cyclosporins / Q000378:metabolism*; D004987:Ethers / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000378:metabolism; D015759:Ionomycin; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D019696:Peptidylprolyl Isomerase; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002352:Carrier Proteins; D003524:Cyclosporins; D004987:Ethers; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015759:Ionomycin; D019696:Peptidylprolyl Isomerase; D013755:Tetradecanoylphorbol Acetate