Sirolimus

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of sirolimus
General
Non-proprietary name Sirolimus
other names
  • SRL
  • Rapamycin
Molecular formula C 51 H 79 NO 13
External identifiers / databases
CAS number 53123-88-9
EC number 610-965-5
ECHA InfoCard 100.107.147
PubChem 5284616
ChemSpider 10482078
DrugBank DB00877
Wikidata Q32089
Drug information
ATC code

L04 AA10

Drug class

Immunosuppressants

properties
Molar mass 914.17 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data

> 2500 mg kg −1 ( LD 50 ,  mouse ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Sirolimus (SRL), also called rapamycin , is an immunosuppressant and mTOR - inhibitor with a macrolide structure (macrocyclic lactone). It is a product of the streptomycete Streptomyces hygroscopicus , a type of bacteria that was first isolated from the soil of Rapa Nui (Easter Island). Sirolimus and tacrolimus are related substances, which, however, were isolated from different streptomycetes and also have different mechanisms of action.

Applications

Sirolimus is used after kidney transplants, usually in combination with ciclosporin and corticosteroids , to prevent organ rejection. One of the important side effects is the wound healing disorder. In contrast to ciclosporine or tacrolimus , sirolimus is not toxic to the kidneys , which is why it does not contribute to chronic transplant nephropathy .

In cardiology, the anti - proliferative effects of sirolimus are used to prevent re- narrowing ( restenosis ) due to hyperplasia of the vascular intima after implantation of a stent in the coronary arteries . In several studies, stents coated with Sirolimus show the formation of fewer restenoses than conventional metal stents . However, there is a risk of stent thrombosis , since sirolimus also prevents the formation of new neointima and thus platelets can attach to the stent over a longer period of time and close the stent.

Due to its antiproliferative effects on cells, rapamycin has also moved into the field of anti-tumor therapy, as it is believed to be able to inhibit the growth and neovascularization of certain tumors . In 2015, the FDA recognized sirolimus for the treatment of the rare lung disease lymphangioleiomyomatosis in the United States .

Furthermore, sirolimus was shown to be extremely effective in the autoimmune lymphoproliferative syndrome (ALPS) , in which the hyperactive mTor signaling pathway is specifically inhibited in the pathognomonic CD4 - CD8 double negative T cells (DNT).

In biochemistry , sirolimus is used in the chemically induced dimerization of certain fusion proteins .

Life span extension

In a study from 2009, the life span of mice could be extended by 28–38% from the start of treatment, which corresponds to an overall increase in maximum life expectancy of 9–14%. It is also noteworthy that the treated mice were already 20 months old, which corresponds to a human age of around 60 years. Because of the strong immunosuppressive effect - and the associated side effects - of rapamycin, it is generally not possible to transfer the results to humans without further ado. The lifespan of mice has now been increased by 60%.

In the United States, a five-year field trial of rapamycin began in 2016 in over 1,500 dogs weighing over 25 kg.

Potential for Alzheimer's Disease Therapy

In the mouse animal model, rapamycin shows a potentially positive effect against the symptoms of Alzheimer's disease . It is believed that the effect is due to an inhibition of mTOR . Increased deposits of β-amyloid obviously lead to an increased expression of mTOR, while conversely, inhibition of mTOR by rapamycin appears to reduce the concentration of β-amyloid. The mTOR signaling pathway plays a central role in the regulation of protein homeostasis . As early as 2010, Derek Lowe pointed out this option in a small blog post entitled "Rapamycin for Alzheimer's?" In 2014, Chinese scientists also reported that mTOR blockade could extend life and delay the development of Alzheimer's disease. However, there are still many questions to be answered before this active ingredient can be tested in clinical studies.

The development of new active ingredients against Alzheimer's dementia is characterized by many setbacks. Clinical research on the anti-amyloid antibody aducanumab from Biogen was discontinued in March 2019 due to a lack of endpoint data. According to scientists Matt Kaeberlein ( University of Washington , Seattle ) and Veronica Galvan (UT Health San Antonio, Texas), it makes sense to test rapamycin in clinical trials, preferably in patients with MCI (mild cognitive impairment) and in Patients who have just been diagnosed with Alzheimer's disease.

Mechanism of action

Stick model of Sirolimus.

Sirolimus has a different mechanism of action than ciclosporin and tacrolimus , both of which inhibit calcineurin . The immunosuppressive effect of sirolimus (rapamycin), however, comes by with an intracellular cytosolic protein (FKBP12) a complex which forms a 282  kDa large serine / threonine - protein kinase binds and so this protein, mTOR ( mammalian target of rapamycin , known as the “target of rapamycin in mammals”).

In addition, various cytokine- mediated signal transduction pathways can be suppressed, which otherwise originate from mTOR as part of the protein complexes mTORC1 and mTORC2 . As a result , there is no transcription and translation of various proteins, in particular those that promote the proliferation of T lymphocytes in particular . Both their activation and the progression from the G1 phase to the S phase of the T cell cycle is prevented.

Trade names

Rapamune ® , manufacturer: Pfizer

Individual evidence

  1. ↑ a b Datasheet Rapamycin from Streptomyces hygroscopicus at Sigma-Aldrich , accessed on May 29, 2011 ( PDF ).
  2. ↑ JJ Augustine et al .: Use of sirolimus in solid organ transplantation. In: Drugs 67, 2007, pp. 369-391, PMID 17335296 .
  3. ↑ Conversion of rejection prophylaxis to sirolimus - chance of maintaining kidney transplant function for longer. In: Dialyse aktuell 12, 2008, pp. 526-528. doi : 10.1055 / s-0028-1104662 .
  4. ↑ RK Wali and MR Weir: Chronic allograft dysfunction: can we use mammalian target of rapamycin inhibitors to replace calcineurin inhibitors to preserve graft function? In: Curr Opin Organ Transplant 13, 2008, pp. 614-621, PMID 19060552 .
  5. ↑ C. Morath et al .: Sirolimus in renal transplantation. In: Nephrol Dial Transplant 22, 2007, pp. 61-65, PMID 17890266 .
  6. ↑ G. Stallone et al .: There is a choice for immunosuppressive drug nephrotoxicity: Is it time to change? In: J Nephrol 22, 2009, pp. 326-332, PMID 19557709 .
  7. ↑ https://www.europeanpharmaceuticalreview.com/news/32030/rapamune-becomes-first-fda-approved-treatment-for-lymphangioleiomyomatosis-lam/In : European Pharmaceutical Review of June 1, 2015.
  8. ↑ Christian Klemann, Myrian Esquivel, Aude Magerus-Chatinet, Myriam R. Lorenz, Ilka Fuchs: Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome . In: Haematologica . tape 102 , no. 2 , February 1, 2017, p. e52 – e56 , doi : 10.3324 / haematol.2016.153411 , PMID 27789675 , PMC 5286954 (free full text).
  9. ↑ S. Volkl, A. Rensing-Ehl, A. Allgauer, E. Schreiner, MR Lorenz: Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome . In: Blood . tape 128 , no. 2 , July 14, 2016, p. 227-238 , doi : 10.1182 / blood-2015-11-685024 .
  10. ^ DE Harrison, R. Strong, ZD Sharp et al: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice . In: Nature . July 8, 2009. doi : 10.1038 / nature08221 .
  11. ^ J. Rice: First Drug Shown to Extend Life Span in Mammals . In: Massachusetts Institute of Technology (Ed.): Technology Review . July 8, 2009, pp. 1-2. Retrieved July 9, 2009.
  12. ↑ A. Bitto, TK Ito, VV Pineda, NJ LeTexier, HZ Huang, E. Sutlief, H. Tung, N. Vizzini, B. Chen, K. Smith, D. Meza, M. Yajima, RP Beyer, KF Kerr , DJ Davis, CH Gillespie, JM Snyder, PM Treuting, M. Kaeberlein: Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. In: eLife. Volume 5, August 2016, pp., Doi : 10.7554 / eLife.16351 , PMID 27549339 , PMC 4996648 (free full text).
  13. ↑ Elke Bodderas: Rapamycin could give you nine years of life. In: welt.de . June 4, 2016, Retrieved June 8, 2016 .
  14. ↑ Amy Harmon: Dogs Test Drug Aimed at Humans' Biggest Killer: Age. In: nytimes.com. May 16, 2016, accessed June 8, 2016 .
  15. ^ A. Caccamo, S. Majumder, A. Richardson, R. Strong, S. Oddo: Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. In: J Biol Chem . 285, 2010, pp. 13107-13120 PMID 20178983 PMC 285710 (free full text).
  16. ↑ Rapamycin reduces Alzheimer's symptoms in mice. In: Spektrumdirekt from February 26, 2010.
  17. ↑ Rapamycin for Alzheimer's? , Blog in Science Translational Medicine by Derek Lowe on April 5, 2010, accessed May 5, 2019
  18. ↑ Chong WangJin-Tai Yu et al .: Targeting the mTOR Signaling Network for Alzheimer's Disease Therapy In: Molecular Neurobiology , Volume 49, February 2014, doi : 10.1007 / s12035-013-8505-8
  19. ↑ Biogen and Eisai to Discontinue Phase 3 ENGAGE and EMERGE Trials of aducanumab in Alzheimer's Disease , Biogen PM, March 21, 2019, accessed May 5, 2019
  20. ↑ Matt Kaeberlein, Veronica Galvan: rapamycin and Alzheimer's disease: Time for a clinical trial? In: Science Translational Medicine , Volume 11, January 2019, doi : 10.1126 / scitranslmed.aar4289
  21. ↑ C. Sabers, M. Martin, G. Brunn, J. Williams, F. Dumont, G. Wiederrecht, R. Abraham: Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. In: Journal of Biological Chemistry. Volume 270, No. 2, January 1995, PMID 7822316 , doi: 10.1074 / jbc.270.2.815 , pp. 815-822.

Web links