1. By: Jubair Aziz, Jing Nan Qiao, Bita Janzadeh
Sirolimus
By: Jubair Aziz, Jing Nan Qiao, Bita Janzadeh
PHM Fall 2017
Instructor: Dr. Jeffrey Henderson

2. What is Sirolimus? a.k.a. Rapamycin immunosuppressant agent used to
prevent organ transplant rejection
Product of streptomyces hygroscopicus
FDA approved as an anti-rejection drug for
kidney transplants in 1997
site of action: mTOR (mechanistic target of rapamycin)

3. mechanistic target of rapamycin (mTOR)
289-kD Ser/Thr protein kinase
Mediates various cell processes, including cell growth, cell proliferation, protein synthesis, transcription, and more
Sirolimus inhibits function of mTOR → immune cells don’t proliferate

4. Allograft Rejection
MHC (major histocompatibility complex) molecules bind to graft and display antigens to T cell receptors
→ recognize as foreign
→ T cell activation
Via autocrine signalling, IL-2 (cytokine signalling molecule) produced
→ activation/proliferation of lymphocytes
→ transplanted tissue destroyed
Sirolimus inhibits function of mTOR → halts IL-2 mediated T cell activation and proliferation
→ suppressed immune system, tissue not rejected

5. Mechanism of Action Sirolimus binds to a class of
protein called FK Binding Protein.
The sirolimus:FKPB12 complex act
on mTOR, which inhibits mTOR signalling
pathways

7. mTOR and S6K1
mTOR activates S6K1, which phosphorylates the S6 protein of the 40s subunit of ribosome
Activation of S6 dramatically increases the translation of a class of polypyrimidine mRNA.
Examples of protein coded include eEF2 (eukaryotic elongation factor 2) involved in translation.
Blocking mTOR will block protein translation
Decreasing synthesis of cell-cycle proteins halts cell cycles and prevents IL 2 mediated T cell proliferation.

9. mTOR and 4EBP1 When eIF4E binding protein 1
is phosphorylated, it dissociates from
eIF4E and allows for translation
Initiation.
Active mTOR complex
phosphorylates eIF4E binding protein 1.
Rapamycin inhibits the action
of mTOR, therefore inhibiting
phosphorylation, preventing
translation initiation.

11. ⇆ mTOR and the cell cycle
Inhibiting protein translation leads to shortage of proteins at G1 phase
Cells fail to progress to S phase ⇆

12. Effects of Sirolimus
mTOR pathway inhibition leads to suppression of T cells
Suppression of CD4 effector T cells, promotion of Tregs → Suppression in lymphocyte function
mTOR pathway is common to multiple cell lines → Proliferation of other cells
Sirolimus binding does not affect calcineurin
Relative lack of nephrotoxicity
Enhances toxicity of calcineurin inhibitors

13. Side Effects Hyperlipidemia Myelosuppression Impaired wound healing
Proteinuria

14. A promising drug
Promising drug for transplantation, anticancer and novel vaccination strategies

15. Summary Slide
Sirolimus (aka rapamycin) is an immunosuppressant agent used to prevent organ transplant rejection
Inhibits the function of mTOR, a protein controls the growth/proliferation of various cells
halts IL-2 mediated T cell activation and proliferation through mTOR
Sirolimus:FKBP12 acts on mTOR
Sirolimus prevents activation of S6K1 and phosphorylation of S6 protein in the 40S subunit, inhibiting translation initiation.
Sirolimus inhibits phosphorylation of 4EBP and prevents eIF4E release from 4EBP,also inhibiting translation initiation.
Sirolimus stops the cell at the G1 phase and makes it unable to proceed to S phase
mTOR pathway inhibition leads to suppression of T cells
Sirolimus does not affect calcineurin, but enhances nephrotoxicity of calcineurin inhibitors
A balance needs to be found between immunologic tolerance to organ allograft and immune response against malignant cancers

16. References
Sehgal, S. (2003). Sirolimus: its discovery, biological properties, and mechanism of action. Transplantation Proceedings, 35(3), pp.S7-S14.
Augustine, J., Bodziak, K. and Hricik, D. (2007). Use of Sirolimus in Solid Organ Transplantation. Drugs, 67(3), pp
Geissler, E., Schlitt, H. and Thomas, G. (2008). mTOR, Cancer and Transplantation. American Journal of Transplantation, 8(11), pp
Tsang, C.K., Qi H., Liu L.F., Zheng X.F. (2007). Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discovery Today. 12 pp.112–124.
Säemann M.D., Haidinger M., Hecking M., Hörl W.H., Weichhart T. (2009). The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am J Transplant. 9(12), pp.2655–61.
Garret et al. (2013). First Canadian Edition. Nelson education p