Sirolimus

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Sirolimus
Sirolimus.svg
Sirolimus-from-1C9H-3D-sticks.png
Systematic (IUPAC) name
(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
Clinical data
Trade names Rapamune
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 14% (oral solution), lower with high-fat meals; 18% (tablet), higher with high-fat meals[1]
Protein binding 92%
Metabolism Hepatic
Biological half-life 57–63 hours
Excretion Mostly faecal
Identifiers
CAS Number 53123-88-9 YesY
ATC code L04AA10 (WHO) S01XA23 (WHO)
PubChem CID 5284616
DrugBank DB00877 YesY
ChemSpider 10482078 YesY
UNII W36ZG6FT64 YesY
KEGG D00753 YesY
ChEBI CHEBI:9168 N
ChEMBL CHEMBL413 YesY
Synonyms Rapamycin
PDB ligand ID RAP (PDBe, RCSB PDB)
Chemical data
Formula C51H79NO13
Molar mass 914.172 g/mol
Physical data
Solubility in water 0.0026 [2] mg/mL (20 °C)
 NYesY (what is this?)  (verify)

Sirolimus (INN/USAN), also known as rapamycin, is a macrolide (one of a group of drugs containing a macrolide ring) produced by the bacterium Streptomyces hygroscopicus.[3] It has immunosuppressant functions in humans and is used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B cells by inhibiting the production of interleukin-2 (IL-2). Sirolimus is also used as a coronary stent coating.

Sirolimus was isolated for the first time in 1972 by Suren Sehgal and colleagues from samples of Streptomyces hygroscopicus found on Easter Island.[4][5] The compound was originally named rapamycin after the native name of the island, Rapa Nui.[3] Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR. It was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune by Pfizer (formerly by Wyeth).

Mechanism of action[edit]

See also: mTOR inhibitors

Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokines receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells. Tacrolimus and cyclosporine inhibit the secretion of IL-2, by inhibiting calcineurin.

The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR (mechanistic (formerly mammalian) Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).

mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.

Clinical uses[edit]

Prevention of transplant rejection[edit]

The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on October 7, 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.

Sirolimus can also be used alone, or in conjunction with calcineurin inhibitors, such as tacrolimus and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimens. Impaired wound healing and thrombocytopenia are a possible side effects of sirolimus; therefore, some transplant centres prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials.

The absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition. This is determined by taking a blood sample before the next dose, which gives the trough level. However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its pharmacokinetic (PK) profile. PK profiles of SRL and of TAC are unaltered by simultaneous administration. Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both.[6]

Coronary stent coating[edit]

Further information: Drug-eluting stent

The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent was marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher.[7] However, this kind of stent may also increase the risk of vascular thrombosis.[8]

Lymphangioleiomyomatosis[edit]

Sirolimus is indicated for the treatment of lymphangioleiomyomatosis (LAM).[9]

Adverse effects[edit]

The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.[9]

The most common adverse reactions (≥20% occurrence, leading to a 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis, nasopharyngitis, acne, upper respiratory tract infection, dizziness, and myalgia.[9]

The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:[9]

System Adverse effects
Body as a Whole Sepsis, lymphocele, herpes zoster infection, herpes simplex infection
Cardiovascular Venous thromboembolism (pulmonary embolism and deep venous thrombosis), rapid heart rate
Digestive Stomatitis
Hematologic/Lymphatic Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia
Metabolic Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes
Musculoskeletal Bone necrosis
Respiratory Pneumonia, epistaxis
Skin Melanoma, squamous cell carcinoma, basal cell carcinoma
Urogenital Pyelonephritis, ovarian cysts, menstrual disorders (amenorrhea and menorrhagia)

Diabetes-like symptoms[edit]

While sirolimus inhibition of mTORC1 appears to mediate the drug's benefits, it also inhibits mTORC2, which results in diabetes-like symptoms. This includes decreased glucose tolerance and insensitivity to insulin.[10] Sirolimus treatment may additionally increase the risk of type 2 diabetes.[11] In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.[12]

Lung toxicity[edit]

Lung toxicity is a serious complication associated with sirolimus therapy,[13][14][15][16][17][18][19] especially in the case of lung transplants.[20] The mechanism of the interstitial pneumonitis caused by sirolimus and other macrolide MTOR inhibitors is unclear, and may have nothing to do with the mTOR pathway.[21][22][23] The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.[13][24]

Lowered effectiveness of immune system[edit]

There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.[9][25]

Cancer risk[edit]

According to FDA prescribing information, sirolimus may increase an individual's risk for contracting skin cancers from exposure to sunlight or UV radiation, and risk of developing lymphoma.[9]

Impaired wound healing[edit]

Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a high body mass index (i.e., a BMI of ≥30 kg/m2).[9]

Biosynthesis[edit]

The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC.[26] Then, the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin.[27]

Figure 1: Domain organization of PKS of rapamycin and biosynthetic intermediates
Figure 2: Prerapamycin, unbound product of PKS and NRPS
Figure 3: Sequence of "tailoring" steps, which convert unbound prerapamycin into rapamycin

The core macrocycle, prerapamycin (figure 2), is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin. First, the core macrocycle is modified by RapI, SAM-dependent O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a cytochrome P-450 monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450, installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin.[28]

Figure 4: Proposed mechanism of lysine cyclodeaminase conversion of L-lysine to L-pipecolic acid

The biosynthetic genes responsible for rapamycin synthesis have been identified. As expected, three extremely large open reading frames (ORF's) designated as rapA, rapB, and rapC encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively.[26] The gene rapL has been established to code for a NAD+-dependent lysine cycloamidase, which converts L-lysine to L-pipecolic acid (figure 4) for incorporation at the end of the polyketide.[29][30] The gene rapP, which is embedded between the PKS genes and translationally coupled to rapC, encodes for an additional enzyme, an NPRS responsible for incorporating L-pipecolic acid, chain termination and cyclization of prerapamycin. In addition, genes rapI, rapJ, rapM, rapN, rapO, and rapQ have been identified as coding for tailoring enzymes that modify the macrocyclic core to give rapamycin (figure 3). Finally, rapG and rapH have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression.[31] Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which is derived from the shikimate pathway.[26] Note that the cyclohexane ring of the starting unit is reduced during the transfer to module 1. The starting unit is then modified by a series of Claisen condensations with malonyl or methylmalonyl substrates, which are attached to an acyl carrier protein (ACP) and extend the polyketide by two carbons each. After each successive condensation, the growing polyketide is further modified according to enzymatic domains that are present to reduce and dehydrate it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1). Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS. Then, the NSPS cyclizes the polyketide, giving prerapamycin, the first enzyme-free product. The macrocyclic core is then customized by a series of post-PKS enzymes through methylations by MTases and oxidations by P-450s to yield rapamycin.

Research[edit]

A plaque, written in Portuguese, commemorating the discovery of sirolimus on Easter Island, near Rano Kau

Cancer[edit]

The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting[32] or otherwise promote tumor regression in clinical trials.[33] Sirolimus seems to lower the cancer risk in some transplant patients.[34]

Sirolimus was shown to inhibit the progression of dermal Kaposi's sarcoma in patients with renal transplants. Other mTOR inhibitors, such as temsirolimus (CCI-779) or everolimus (RAD001), are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma. However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs.[35]

A combination therapy of doxorubicin and sirolimus has been shown to drive AKT-positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs, such as doxorubicin or cyclophosphamide. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; eIF4E-expressing lymphomas are not sensitive to sirolimus.[36][37][38][39]

Tuberous sclerosis complex[edit]

Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that leaves sufferers prone to benign tumor growth in the brain, heart, kidneys, skin, and other organs. After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant-cell astrocytomas in children and angiomyolipomas in adults, many US doctors began prescribing sirolimus (Wyeth's Rapamune) and everolimus (Novartis's RAD001) to TSC patients off-label. Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in the United States.[40]

Most studies thus far have noted that tumors often regrew when treatment stopped. Theories that claim the drug ameliorates TSC symptoms such as facial angiofibromas and autism are a matter of current research in animal models.[medical citation needed]

Effects on longevity[edit]

Rapamycin was first shown to extend lifespan in eukaryotes in 2006.[41] Powers et al. showed a dose-responsive effect of rapamycin on lifespan extension in yeast cells. Building on this and other work, in a 2009 study, the lifespans of mice fed rapamycin were increased between 28 and 38% from the beginning of treatment, or 9 to 14% in total increased maximum lifespan. Of particular note, the treatment began in mice aged 20 months, the equivalent of 60 human years. This suggests the possibility of an effective antiaging treatment for humans at an already-advanced age, as opposed to requiring a lifelong regimen beginning in youth.[42] Rapamycin has subsequently been shown to extend mouse lifespan in several separate experiments,[43][44] and is now being tested for this purpose in nonhuman primates (the marmoset monkey),[45] and with an ongoing attempt to organize a study in dogs.[46] The Dog Aging Project is funded by pet owners.[47]

Because rapamycin at high doses can suppress the immune system, people taking rapamycin for transplant or cancer therapy are more susceptible to dangerous infections. Yet paradoxically, rapamycin was shown to enhance the ability of aging mice to mount an immune response to a vaccine against tuberculosis.[48] A similar immunological "rejuvenating" effect was later documented in elderly humans administered a rapamycin analog prior to influenza vaccination),[49] further fueling optimism for the potential of mTOR as a target for anti-aging drugs for humans. Recent work in mice suggests that intermittent treatment with rapamycin may substantially reduce side effects while still promoting health and extending lifespan.[50][51][52][53][54][55] Co-administration of the anti-diabetes drug metformin may further increase the lifespan of rapamycin-treated mice.[56]

However, it is not known whether rapamycin will have similar lifespan-lengthening effects in humans, and study authors caution that the drug should not be used by the general population for this use.[57]

Decreased TOR activity has been found to increase life span in S. cerevisiae, C. elegans, and D. melanogaster.[58][59][60][61] The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice.[62][63][64]

It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.[58][59] It is believed that this is achieved by limiting the essential amino acid leucine, a potent activator of mTOR.[citation needed] The administration of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.[65]

According to the free radical theory of aging,[66] reactive oxygen species cause damage of mitochondrial proteins and decrease of ATP production. Subsequently, via ATP sensitive AMPK, the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ribosome.[67] Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration.[68] These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates glycolysis[68] and removal of dysfunctional cellular components via autophagy.[66]

Tuberous sclerosis in mice, with possible relevance to autism[edit]

In a study of sirolimus as a treatment for tuberous sclerosis, researchers observed improvements in TSC symptoms which overlap with autism. The researchers discovered that sirolimus regulates one of the same proteins the TSC gene does, but in different parts of the body. They decided to treat mice three to six months old (adulthood in mice lifespans); this increased the TSC mice's intellect to about that of normal mice in as little as three days.[69]

Alzheimer's in mice[edit]

Sirolimus reduced brain lesions and prevented the decline of performance in the water maze in mice with a mouse model of Alzheimer's.[70] Recent studies have observed a protective effect against Alzheimer's Disease in preventing cognitive deficits and reducing amyloid-β levels in mouse models. [71]

Muscular dystrophy in mice[edit]

Researchers at Washington University School of Medicine in St. Louis observed that nanoparticles coated in sirolimus increases grip strength by 30% and significantly increases cardiac function in mice. The nanoparticle consists of a core of perfluorocarbon and are 200 nm in diameter. The nanoparticle accumulates in areas of inflammation, in this case the muscles where it releases a small dose of sirolimus. This suppresses the immune system and promotes autophagy.[72]

Systemic lupus erythematosus in mice and humans[edit]

Sirolimus improves disease activity and dependence on prednisone in systemic lupus erythematosus (SLE) patients resistant or intolerant to immunosuppressant medications. Sirolimus acts through blocking the activation of its molecular target, the mechanistic target of rapamycin complex 1 (mTORC1). The activation of mTORC1, which is associated with suppression of mTORC2, results in the expansion of proinflammatory CD4-CD8- double-negative (DN) T lymphocytes. These DN T cells produce inflammatory cytokines, interleukin-4 (IL-4) and interleukin-17, and they exhibit predisposition to proinflammatory cell death through necrosis. Increased IL-4 production is responsible for activation of autoantibody-producing B lymphocytes in SLE.[73][74][75][76][77] Sirolimus also blocks disease in lupus-prone mice by reversing the activation of mTORC1.[78] Prospective clinical trial in SLE patients with sirolimus is ongoing.

Other afflictions[edit]

Studies in vitro in mice and in humans suggest sirolimus inhibits HIV replication through different mechanisms, including downregulation of the coreceptor CCR5[79] and the induction of autophagy.[80]

In addition, sirolimus is currently being assessed as a therapeutic option for autosomal-dominant polycystic kidney disease (ADPKD). Case reports indicate sirolimus can reduce kidney volume and delay the loss of renal function in patients with ADPKD.[81]

Sirolimus has also been used in preliminary research to combat progeria, a rare disorder that causes individuals to age at an exceedingly rapid pace, leading to an extremely compromised cell-damage repair capacity and typically resulting in death in the early teenage years due to causes which are generally associated with old age such as heart disease or stroke.[82]

Applications in biology research[edit]

Rapamycin is used in biology research as an agent for chemically induced dimerization.[83] In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin-binding FRB domain from mTOR and the other of which contains an FKBP domain. Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP. In this way, rapamycin can be used to control and study protein localization and interactions.

References[edit]

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