Drugs Xagena
Researchers have found that Salicylic acid targets the activities of HMGB1, an inflammatory protein associated with a wide variety of diseases, offering hope that more powerful Aspirin-like drugs may be developed.
Aspirin is one of the oldest and most commonly used medicines, but many of its beneficial health effects have been hard for scientists and physicians to explain.
A recent study conducted by researchers at the Boyce Thompson Institute ( BTI ), in collaboration with colleagues at Rutgers University and San Raffaele University and Research Institute, has shown that Aspirin's main breakdown product, Salicylic acid, blocks HMGB1, which may explain many of the drug's therapeutic properties.
The protein, HMGB1, is associated with many prevalent, devastating diseases in humans, including rheumatoid arthritis, heart disease, sepsis and inflammation-associated cancers, such as colorectal cancer and mesothelioma.
Aspirin's pain relieving effects have long been attributed to its ability to block the enzymes cyclooxygenase 1 and 2, which produce prostaglandins ( hormone-like compounds that cause inflammation and pain ) a discovery that netted its discoverer, John Vane, a Nobel prize.
However, the body rapidly converts Aspirin (Acetylsalicylic acid ) to Salicylic acid, which is a much less effective inhibitor of cyclooxygenase 1 and 2 than Aspirin.
Nonetheless, it has similar pharmacological effects as Aspirin, suggesting that salicylic acid may interact with additional proteins.
Some researchers have suggested that Salicylic acid should be called vitamin S, due to its tremendous beneficial effects on human health.
In the current study, published in Molecular Medicine, researchers discovered the interaction between Salicylic acid and HMGB1 by screening extracts prepared from human tissue culture cells to find proteins that could bind to Salicylic acid. They identified one of these proteins as HMGB1. These screens have also identified a key suspect in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, plus approximately two dozen additional candidates that have yet to be characterized.
In the body, HMGB1 is normally found inside the nucleus, but can enter the blood stream when released from injured tissues or secreted by certain immune or cancer cells. The protein in the blood stream triggers inflammation by recruiting immune cells involved in preventing infections and repairing damaged tissues. HMGB1 also activates these recruited immune cells to express genes that code for pro-inflammatory cell-signaling proteins called cytokines.
To further investigate the interactions between Salicylic acid and HMGB1's role in the body, Daniel Klessig at BTI worked with Marco Bianchi of San Raffaele University and Research Institute, who initially discovered that HMGB1 is a trigger of inflammation.
Using assays that measured the effects of Salicylic acid on the recruitment and activation of immune cells, they showed that Salicylic acid could block both of these functions at concentrations similar to those found in people on low-dose Aspirin.
The Klessig group identified two derivatives of Salicylic acid, which are far more effective than Salicylic acid in blocking HMBG1's pro-inflammatory activities.
They synthesized one compound in the lab, while a second was isolated from a licorice plant used as a Chinese medicinal herb.
Analyses of these derivatives revealed that appropriate modifications of Salicylic acid can enhance the strength of its interaction with HMGB1, providing the basis for rational design of new Aspirin-like molecules. ( Xagena )
Source: Boyce Thompson Institute, 2015
XagenaMedicine_2015
