Disease relevance of SANGLIFEHRIN A

• Sanglifehrin A (SFA) is a novel immunosuppressant isolated from Streptomyces sp. that binds strongly to the human immunophilin cyclophilin A (CypA) [1].
• In the isolated adult myocyte model, SFA was shown to inhibit mPTP opening in the setting of oxidative stress, represented by an increase in the ROS threshold required to induce: mitochondrial membrane depolarisation (from 269+/-21 to 777+/-100 s; p<0.001) and rigour contracture (from 613+/-14 to 1329+/-129 s; p<0.001) [2].

High impact information on SANGLIFEHRIN A

• Structure of human cyclophilin A in complex with the novel immunosuppressant sanglifehrin A at 1.6 A resolution [1].
• The novel cyclophilin binding compound, sanglifehrin A, disassociates G1 cell cycle arrest from tolerance induction [3].
• The novel cyclophilin-binding drug sanglifehrin A specifically affects antigen uptake receptor expression and endocytic capacity of human dendritic cells [4].
• Sanglifehrin A (SfA), like CsA, exerts its immunosuppressive action by binding to cyclophilin A but at a different site from CsA, and unlike the latter, SfA does not inhibit calcineurin activity [5].
• Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A [5].

Biological context of SANGLIFEHRIN A

• Unlike other genotoxic drugs, sanglifehrin A does not cause DNA damage, making it a unique natural product that is capable of activating the NFkappaB signaling pathway without affecting DNA [6].
• We report that sanglifehrin A is capable of activating the tumor suppressor gene p53 at the transcription level, leading to up-regulation of p21 that then binds and inhibits the cylcinE-Cdk2 complex [6].
• 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 [7].
• We examined the effect of SFA on mPTP opening directly, using a myocyte model of oxidative stress [2].
• Sanglifehrin A inhibits M-CSF-dependent macrophage proliferation by arresting the G1 phase of the cell cycle but does not affect cell viability [8].

Anatomical context of SANGLIFEHRIN A

• It has been previously shown that sanglifehrin A specifically blocks T cell proliferation in response to interleukin 2 by inhibiting the appearance of cell cycle kinase activity cyclinE-Cdk2 [6].
• We hypothesised that the novel immunosuppressant, sanglifehrin-A (SFA), given at the time of reperfusion, protects the myocardium from ischaemia-reperfusion injury, by suppressing mPTP opening [2].
• Immunosuppressive activity of the immunophilin-binding drug Sanglifehrin A in human whole blood: potent inhibition of interleukin-6 produced by lymphocytes and monocytes [9].

Associations of SANGLIFEHRIN A with other chemical compounds

• METHODS: Isolated perfused rat hearts were subjected to 35 min ischaemia/120 min reperfusion, and were treated with (1) SFA (1.0 microM) or (2) DMSO vehicle for the first 15 min of reperfusion or (3) SFA (1.0 microM) after the first 15 min of reperfusion [2].
• This may be mediated either by a direct interaction with the MPTP [e.g., by Cyclosporin A (CsA) and Sanglifehrin A (SfA)], or indirectly by decreasing calcium loading and reactive oxygen species (ROS; key inducers of pore opening) or lowering intracellular pH [10].

Gene context of SANGLIFEHRIN A

• The CypA inhibitor cyclosporin A and non-immunosuppressive PPIase inhibitors such as NIM811 and sanglifehrin A block expression of Vpr without affecting pre- or post-translational events such as transcription, intracellular transport, or virus incorporation of Vpr [11].
• Further analysis of different elements in the p53 promoter showed that sanglifehrin A activates p53 transcription primarily through the activation of the transcription factor NFkappaB by activating IkappaB kinase in a manner that is similar to several genotoxic agents [6].
• In the early steps of M-CSF signaling, SfA inhibits the phosphorylation of Raf-1 and the external regulated kinases (ERK)1/2 and mitogen-activated protein kinase phosphatase-1, which are required for proliferation [8].
• Sanglifehrin A, a novel cyclophilin-binding immunosuppressant, inhibits IL-2-dependent T cell proliferation at the G1 phase of the cell cycle [12].

Analytical, diagnostic and therapeutic context of SANGLIFEHRIN A

• RESULTS: In the isolated perfused heart model, SFA, given during the first 15 min of post-ischaemic reperfusion, reduced the infarct-risk volume ratio from 43.9+/-2.5% in the control group to 23.8+/-4.2% with SFA (p=0.001) [2].
• Compound 2 shows intracellular cyclophilin (CyP)-binding and immunosuppressive activity in the mixed-lymphocyte reaction (MLR) similar to that of sanglifehrin A (1) [13].
• Sanglifehrin A Blocks Key Dendritic Cell Functions In Vivo and Promotes Long-Term Allograft Survival Together with Low-Dose CsA [14].

References