Retention of immunosuppressant activity in an ascomycin analogue lacking a hydrogen-bonding interaction with FKBP12.
C24-Deoxyascomycin was prepared in a two-step process from ascomycin and evaluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, was likewise evaluated. Despite lacking the hydrogen-bonding interactions associated with the C24-hydroxyl moiety of ascomycin, C24-deoxyascomycin was found to be equipotent to the parent compound both in its immunosuppressive potency and in its interaction with the immunophilin, FKBP12. Conversely, Delta(23,24)-dehydroascomycin which also lacks the same hydrogen-bonding interactions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomenon at the molecular level. The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation.
Wiedeman
P E
PE
Abbott Laboratories, Pharmaceutical Products Division, 200 Abbott Park Road, Department 47N, Building AP-52N, Abbott Park, Illinois 60064-6217, USA.
Fesik
S W
SW
Petros
A M
AM
Nettesheim
D G
DG
Mollison
K W
KW
Lane
B C
BC
Or
Y S
YS
Luly
J R
JR
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D006965:Hyperplasia; D020104:Immunophilins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009713:Nucleotidyltransferases / Q000235:genetics; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins
C400076:C24-deoxyascomycin; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; C058028:immunomycin; D009713:Nucleotidyltransferases; C028984:3-deoxy-manno-octulosonate cytidyltransferase; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus