Rapamycin Molecule - Sirolimus

Ball and Stick Model for Rapamycin Molecule

Rapamycin also known as Sirolimus has become one of the most talked about and researched small molecules in recent years. It is a compound that in nature is produced by the soil bacterium Streptomyces which was first found in 1965 in a soil sample from Easter Island. Rapamycin was first developed ias an antifungal agent, as it proved effective in suppressing yeast growth. However, it was soon discovered that it also acted as an immunosuppressant, and it has since been used to protect organ transplant patients from organ rejection."... More years went by, and, in 1999, rapamycin received US FDA approval as an immunosuppressant for organ transplants. A derivative was approved to treat kidney cancer in 2007. Then, in 2009, researchers at Jackson Laboratories in Maine discovered the drug’s “fountain of youth” attributes—it extended the lives of lab mice by 6 months or more..." see ref 1. Rapamycin holds the distinction of having been one of the first drugs to have its target identified biochemically: the aptly named protein “mammalian target of rapamycin,” or mTOR.[2]

Structure

Rapamycin Molecular Structure

Rapamycin is a macrolides, compounds that contain large (14–16-membered) lactone rings and reduced saccharide substituents created by bacteria. Many macrolides, such as erythromycin and azithromycin, have been formulated into commercial antibiotics [1]

Mechanism of Action as an Anti-Aging Molecule

Mammalian target of rapamycin (mTOR -- mechanistic target of rapamycin) is a kinase at a key signalling node that integrates information regarding extracellular growth factor stimulation, nutrient availability and energy supplies. Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12. The FKBP12–rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.

Structure of rapamycin (A) and (B) rapamycin bound to its protein partners FKBP12 and FRB of mTOR. (PDB 1NSG [3]).

Combination Therapies using Rapamycin to slow Aging

The researchers were building on previous studies finding that lithium, trametinib and rapamycin can each extend lifespan in fruit flies (Drosophila), which is supported by other preliminary evidence in mice, worms, and cells, and observational findings in people.

The three drugs all act on different cellular signalling pathways that together form the nutrient sensing network, which is conserved across evolution from worms and flies all the way to humans. This network adjusts what the body is doing in response to changes in nutrient levels. The three drugs in question act on different proteins of this network to slow the ageing process and delay the onset of age-related death.

"...For the latest study, the researchers gave fruit flies doses of lithium, trametinib and rapamycin, separately and in combination. Each drug individually extended lifespan by an average of 11%, while pairing two drugs extended lifespan by roughly 30%. When the three drugs were combined, the fruit flies lived 48% longer than flies in a control group that were not given the treatment..." [4]

REFERENCES

1- Rapamycin -- I may have wandered into the Fountain of Youth. What molecule am I?July 25, 2016.

2- Is Rapamycin the new aspirin? December 11, 2011.

3- Protein translocation as a tool: The current rapamycin story-- July 2012.

4- A triple drug combination targeting components of the nutrient-sensing network maximizes longevity August 1, 2019