Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data.
Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC(50) = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C(26)=C(27) exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC(50) = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 A of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.
Sedrani
Richard
R
Transplantation Research, Novartis Pharma AG, S-507.312, CH-4002 Basel, Switzerland.
Kallen
Jörg
J
Martin Cabrejas
Luisa M
LM
Papageorgiou
Charles D
CD
Senia
Francesco
F
Rohrbach
Stefan
S
Wagner
Dieter
D
Thai
Binh
B
Jutzi Eme
Anne-Marie
AM
France
Julien
J
Oberer
Lukas
L
Rihs
Grety
G
Zenke
Gerhard
G
Wagner
Jürgen
J
D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D021984:Cyclophilin A / Q000737:chemistry* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D007166:Immunosuppressive Agents; D007783:Lactones; D013141:Spiro Compounds; C121329:sanglifehrin A; D021984:Cyclophilin A