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Rapamune: a novel macrolide immunosuppressant for transplantation

Rapamune (sirolimus, rapamycin) is a macrocyclic natural product that has potent immunosuppressive and antiproliferative properties. It was initially identified as an antifungal agent and further pharmacological evaluation revealed its immunosuppressive activity in a rat model of T-cell-mediated autoimmune disease. Additional in vitro and in vivo pharmacology studies demonstrated that Rapamune was a potent immunosuppressive and antiproliferative agent that prevented allograft rejection in virtually all animal models of organ transplantation. The macrocyclic immunosuppressive agents, including Rapamune, cyclosporin and tacrolimus (FK506) bind to specific cytosolic proteins called immunophilins to generate an immunosuppressive complex. Rapamune and the structurally related immunosuppressive macrolide tacrolimus bind to an identical family of immunophilins called FK506 binding proteins (FKBPs), whereas cyclosporin binds to cyclophilin. The complex of cyclosporin or tacrolimus with their respective immunophilins inhibits calcineurin, a Ca2 +/calmodulin-dependent serine/ threonine phosphatase required for the production of cytokines, specifically interleukin-2 (IL-2), and for the early activation of T cells (Go to G1). The mechanism of action of Rapamune is distinct from that of cyclosporin and tacrolimus. Although Rapamune also binds to FKBP12, in contrast to FK506, the Rapamune:FKBP complex has no effect on calcineurin activity. Rather, this complex binds to a specific cell cycle regulatory protein called the 'mammalian target of rapamycin' (mTOR) and inhibits its activation. It is likely that phosphorylationmediated activation of one or more phosphatases or kinases by mTOR is the first step in the cascade of events that are affected by Rapamune. The inhibition of mTOR (mTor is also known as FRAP, SEP, and RAFT) suppresses cytokine-driven (IL-2, IL-4, IL-7, and IL-15) T-cell proliferation, inhibiting the progression from G1 to S phase of the cell cycle. The preclinical toxicity of Rapamune was evaluated extensively in laboratory animals, primarily rats and monkeys. The majority of effects that occurred were similar to those seen after other compounds of this class, such as cyclosporin and tacrolimus, or