Synthesis, conformation, and immunosuppressive activity of a conformationally restricted cyclosporine lactam analogue.
Cyclosporine A (CsA, 1), an immunosuppressive cyclic undecapeptide, in apolar solvents adopts a II' beta-turn at the Sar3-MeLeu4 residues. [D-Proline3]Cs has been reported to be a nonimmunosuppressive analogue in which the II' beta-turn is retained. In order to determine if this loss of activity is caused by steric hindrance between the Cs analogue and its receptor or is caused by a change in the peptide conformation, an analogue that stabilizes a II' beta-turn has been synthesized, [lactam3,4]Cs. We also have studied the solution conformation of two other analogues, [D-MeAla3]Cs and [L-MeAla3]Cs. The conformations have been established by 1D difference NOE and 2D (NOESY or ROESY) NMR. The conformations of [lactam3,4]Cs and [D-MeAla3]Cs are indistinguishable from that of CsA in solution. [L-MeAla3]Cs was found to adopt a conformation with a cis amide bond between Sar3 and MeLeu4. The inhibition of concanavalin A stimulated thymocytes by CsA, [D-MeAla3]Cs, [L-MeAla3]Cs, and [lactam3,4]Cs gave IC50 values (nM) of 5, 6, 100, and 100, respectively. The weak immunosuppressive activity of [lactam3,4]Cs possessing the II' beta-turn suggests that the loss of activity for 4 is due to steric hindrance with the Cs receptor.
Aebi
J D
JD
University of Wisconsin, School of Pharmacy, Madison 53706.
Guillaume
D
D
Dunlap
B E
BE
Rich
D H
DH
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003208:Concanavalin A / Q000494:pharmacology; D003524:Cyclosporins / Q000138:chemical synthesis* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007165:Immunosuppression Therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D012997:Solvents; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013696:Temperature
D003524:Cyclosporins; D012997:Solvents; C056978:8-(N-methylalanine)cyclosporin A; D003208:Concanavalin A; C056977:cyclosporin lactam(3,4)