Source: Thailand Medical News Jan 06, 2020 4 years, 10 months, 2 weeks, 1 day, 17 hours ago
Researchers from Boyce Thompson Institute have discovered 95 potential new human protein targets for
salicylate compounds and provide a roadmap for future drug development against dozens of diseases.
Individuals have used
aspirin to treat pain, fever and inflammation for more than a century, and the drug is also used to reduce the risk of strokes, heart attacks and some cancers. An estimated 120 billion
aspirin tablets are taken worldwide each year, but how it works is still only partially understood.
Dr Dan Klessig, a faculty member at Boyce Thompson Institute, has long suspected that aspirin’s broad effects are due in part to its primary metabolite,
salicylic acid (
SA). He reached this conclusion because humans metabolize
aspirin into
salicylic acid within minutes, and for nearly 50 years synthetic
salicylic acid was used to treat pain, fever and i
nflammation before the advent of
aspirin.
Furthermore, for millennia many cultures throughout the world have treated pain, fever and
inflammation with
salicylic acid-rich plants such as willow, meadowsweet and poplar and continue to do so today.
To really find clues as to how the compound works, Dr Klessig led a group of researchers to identify human proteins that bind to
salicylic acid and have their activity altered as a result. The BTI team also created a detailed network that links the newly discovered
salicylic acid-binding proteins to dozens of human diseases, such as Alzheimer’s disease, Type II diabetes and arthritis.
The study results, published in
Scientific Reports offer drug and nutraceutical developers a roadmap with multiple avenues for future research on new targets of aspirin and
salicylic acid, and on novel, more potent synthetic or natural plant-derived
salicylic acid derivatives.
Dr Klessig told
Thailand Medical News, “There are more potent derivatives of
salicylic acid that could be made, as well as some present in medicinal plants such as licorice, that have the potential to treat a host of diseases. I think there is such untapped wealth here.”
Dr Hyong Woo Choi, first author agrees and added, “Based on our current research,
salicylic acid might have effects on several developmental, neurological, psychiatric, ophthalmological and muscular diseases, as well as on cancer.”
Dr Choi, currently an Assistant Professor in the Department of Plant Medicals at South Korea’s Andong National University, was a senior research associate in Dr Klessig’s lab when the study was done.
The research study was an outgrowth of three decades of work by Dr Klessig, beginning with his 1990
Science paper describing how plants produce
salicylic acid to protect themselves from v
iral infections and other pathogens.
Dr Klessig added, “All plants contain
salicylic acid, and plant-based diets result in almost as much
salicylic acid in the body as taking a baby
aspirin each day.We evolved eating plants, so it’s not surprising that
salicylic acid affects our physiology.”
To assess how
salicylic acid works in humans, Dr Klessig and his team used a novel screen to identify about 2,000 human proteins that bind to the
salicylic acid derivative 4azSA. The researchers partnered with Dr Adrian Powell and Dr Susan Strickler at the BTI Computational Biology Center (BCBC) to narrow the pool to 95 candidate
salicylic acid-binding proteins (
cSABPs), which were the most highly enriched in the screen. They fell into five broad physiological categories, including protein metabolism and immunity.
Two human proteins,
ENO1 and
PKM2, topped the list. “These two proteins are important because they’re involved in the last two steps of glycolysis,” Dr Klessig said.
Typically, Glycolysis is a fast, inefficient metabolic pathway used to produce energy from glucose in the absence of oxygen. Some cancer cells utilize glycolysis even when oxygen is present to facilitate their growth, which might be exploitable for
cancer treatment.
Dr Choi and co-workers confirmed that
salicylic acid and a much more potent
salicylic acid derivative from the licorice plant,
amoB1, bound to
ENO1 and
PKM2, thereby blocking their activity in human cells. “These findings suggest
salicylic acid can mediate anti-cancer and anti-inflammatory effects,” Dr Choi said.
Dr Powell added, “In the BCBC, we use bioinformatics to make predictions. So it’s pretty satisfying and exciting that the group was able to validate the top two candidate targets in the lab.”
To assist predict other conditions that
salicylic acid might treat, Dr Choi searched a publicly available database containing gene–disease associations and found the genes encoding the 95
cSABPs were implicated in over 1,100 diseases across 22 physiological categories.
These study results provide researchers with a roadmap to further investigate the
cSABPs in disease and could also encourage drug and nutraceutical researchers to take a closer look at other plant-produced
salicylic acid derivatives.
Dr Klessig added, “So many medicinal plants are being used to treat pain, fever and inflammation; I bet that the active ingredient in many of them is a
salicylic acid derivative.”
Dr Klessig is also an adjunct professor of Plant Pathology and Plant-Microbe Biology at Cornell University. Strickler is director of BCBC and a senior research associate at BTI, and Powell is a postdoctoral scientist in her group. Co-author Frank Schroeder is a professor at BTI and in the Department of Chemistry and Chemical Biology at Cornell University.
Reference : Choi, H.W., Wang, L., Powell, A.F. et al. A genome-wide screen for human salicylic acid (SA)-binding proteins reveals targets through which SA may influence development of various diseases. Sci Rep 9, 13084 (2019) doi:10.1038/s41598-019-49234-6 https://doi.org/10.1038/s41598-019-49234-6 
