Cyclosporin A (CsA) is a widely used immunosuppressant drug. Its immunosuppressive activity occurs through the inhibition of the protein phosphatase calcineurin via formation of a ternary complex with cyclophilin A (CypA). CsA also inhibits endothelial cell proliferation and angiogenesis. This has been thought to occur through calcineurin inhibition as well. However, CsA is also a potent inhibitor of cyclophilins, a class of prolyl isomerases. Because calcineurin inhibition requires binding and therefore inhibition of CypA, the relative contributions of calcineurin and cyclophilin inhibition in antiangiogenesis have not been addressed. We have taken a chemical biology approach to explore this question by dissociating the two activities of CsA on the molecular level. We have identified a non-immunosuppressant analog of CsA which does not inhibit calcineurin but maintains inhibition of endothelial cell proliferation and in vivo angiogenesis. The same analog also maintains inhibition of all tested cyclophilin isoforms. We also show that a second structurally distinct cyclophilin inhibitor is sufficient to block endothelial cell proliferation. These results suggest that the inhibition of cyclophilins may play a larger role in the anti-angiogenic activity of CsA than previously believed, and that cyclophilins may be potential anti-angiogenic drug targets.
- Received February 21, 2011.
- Revision received May 3, 2011.
- Accepted May 5, 2011.
- The American Society for Pharmacology and Experimental Therapeutics