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Transplantation
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Jonathon Olsburgh, Rhana H. Zakri
SirolimusIsolated from Streptomyces hygroscopicus found on Easter Island or Rapa Nui (hence, the name Rapamycin).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Rapamycin (SirolimusTM, RapamuneTM) was the first mTOR inhibitor to be discovered (Figure 6.95). It is a macrolide antibiotic produced by Streptomyces hygroscopicus and was discovered in soil taken from Rapa Nui (Easter Island, Chile). Since the mid-1970s it was known mainly as an antifungal agent, but in the 1990s, after the discovery of its immunosuppressive effects, it was developed by Wyeth and approved as an anti-rejection drug for use in kidney transplant patients under the brand name RapamuneTM. Its antitumor properties were observed subsequently, and it was shown to inhibit the progression of dermal Kaposi’s sarcoma (KS) in patients with renal transplants. However, a clinical development program for rapamycin itself in the cancer area was not pursued due to its unfavorable pharmacological profile.Structures of the mTOR inhibitors rapamycin (RapamuneTM) and the analogues everolimus (AfinitorTM), temsirolimus (ToriselTM), and ridaforolimus. The analogues are sometimes known as the “Rapalogs”.
mTOR Targeting Agents for the Treatment of Lymphoma and Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Andrea E. Wahner Hendrickson, Thomas E. Witzig, Scott H. Kaufmann
A number of mTOR inhibitors are currently undergoing clinical testing as potential anticancer drugs (2–4). The prototype drug in this class is rapamycin (sirolimus), a natural product isolated from a strain of Streptomyces hygroscopicus found in the soil of the Vai Atore region of Easter Island (3,4). Originally identified as an antifungal agent, rapamycin was subsequently shown to inhibit antigen-induced T-cell proliferation, a biochemical effect that presumably contributes to its ability to inhibit graft rejection (17). Sirolimus was approved as an oral immunosuppressant after renal transplantation in the 1990s and was subsequently shown by the National Cancer Institute to inhibit proliferation of several human cancer cell lines.
Host-directed therapies for malaria and tuberculosis: common infection strategies and repurposed drugs
Published in Expert Review of Anti-infective Therapy, 2022
Piyush Baindara, Sonali Agrawal, O. L. Franco
Rapamycin was initially discovered as an antifungal metabolite produced by Streptomyces hygroscopicus. Rapamycin is an attractive candidate for host-directed therapy, as it has proven to be an effective means of suppressing immune responses. Bharatham et al., 2011 found that rapamycin inhibits the growth of P. falciparum in vitro through its binding to the parasite homolog of the mammalian FK506 binding protein [157]. In a mouse model of CM, experimental CM (ECM), rapamycin treatment blocked breakdown of the blood–brain barrier and brain hemorrhaging, and it also decreased the influx of both CD4+ and CD8+ T cells into the brain and the accumulation of parasitized red blood cells in the brain, thus increasing survival [161]. In the case of TB, in vivo studies on mice models demonstrated that rapamycin given at an early age did not significantly change life expectancy or susceptibility to disease; however, when given at a later age, the mice had better survival expectancy [187]. Rapamycin was also given to BCG-vaccinated mice and was reported to have an increased vaccination efficacy against Mtb infection, associated with autophagy, increased antigen presentation, and increased Th1-type immune response [188]. These results indicate that rapamycin may prove to be a highly selective adjunctive therapy for malaria as well as TB.
How can we turn the PI3K/AKT/mTOR pathway down? Insights into inhibition and treatment of cancer
Published in Expert Review of Anticancer Therapy, 2021
Said M. Afify, Aung Ko Ko Oo, Ghmkin Hassan, Akimasa Seno, Masaharu Seno
Among these inhibitors, rapamycin (clinically known as sirolimus) was the first and was discovered in 1975 [103]. It was purified from Streptomyces hygroscopicus, and used as an antifungal drug for some time [104]. Rapamycin is a macrolide compound which contains macrocyclic lactones, its drug target being mTOR. Since inhibition of mTOR can suppress the immune system and cell expansion, rapamycin is currently used as an immunosuppressant and/or antiproliferant. Rapamycin does not bind to mTOR itself but binds to FK506-binding protein 12 (FKBP12) interacting with the FKBP12-rapamycin binding domain (FRB) of mTOR and inhibits mTOR kinase activity [105]. After rapamycin, some similar compounds were also developed. These rapamycin analogs are called ‘rapalogs,’ and they have the same target as rapamycin. Second-generation mTOR inhibitors target the kinase domain of mTOR, whereas third-generation mTOR inhibitors, the newest of all, target the mutations in mTOR expressed in cancer cells [94]. Although there should be lesser side effects of the second- and third-generation rapalogs, they are still on clinical trial, and only rapamycin and the first-generation rapalogs have been approved, and are being clinically used mainly to prevent allograft rejection [106,107]. Further, everolimus is being used for advanced renal cell carcinoma (RCC) and advanced kidney cancer [108,109], and temsirolimus is being used for advanced RCC and mantle cell lymphoma [110].
The role of mTOR in age-related diseases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zofia Chrienova, Eugenie Nepovimova, Kamil Kuca
Collecting soil samples on Easter Island (Rapa Nui) in the 1970s, no one could predict that bacterial cultures of Streptomyces hygroscopicus isolated from these samples would change the way we look at the cell cycle and help us better understand several signalling pathways and cellular processes. The isolated strain demonstrated inhibitory effects on Candida albicans, Microsporum gypseum, Trichophyton granulosum, as well as other gram-positive bacteria, while all gram-negative species were resistant. It was soon shown that S. hygroscopicus produces an antibiotic with antifungal properties, named rapamycin after its place of discovery (Figure 1). This substance, also known by its generic name sirolimus, is a lipophilic macrolide with a white crystalline structure that is insoluble in water but readily soluble in organic solvents1–3.