1nmk: Difference between revisions

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==Overview==

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.

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.

==About this Structure==

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[[Category: rotamase]]

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@@ Line 4: / Line 4: @@
 ==Overview==
-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.
+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.
 ==About this Structure==
@@ Line 24: / Line 24: @@
 [[Category: rotamase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:29:49 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:07:42 2008''