Virginia Tech drug researcher receives $2.2 million NIH grant to further develop ‘fat burning’ molecule
The liver is the most resilient organ in the human body. It can remove toxins from the bloodstream, recycle red blood cells, maintain sugar levels, and it can even regenerate itself. But, when a large amount of fat builds up in the liver, it becomes too inflamed to perform its crucial duties.
This condition is called nonalcoholic steatohepatitis, or NASH for short. It is a type of fatty liver disease that is characterized by inflammation, fat accumulation, and scarring.
Worse yet, much like poison ivy that hides among other vines, poor diagnostics tools for NASH and symptoms that look like general obesity or metabolic disease make it a “silent disease,” able to inflict permanent damage years before it is diagnosed. An estimated 30 million people in the U.S. have NASH, and there are no FDA approved drugs to treat it.
Webster Santos, a professor of chemistry in the College of Science at Virginia Tech, has received a $2.2 million grant from the National Institutes of Health to further his recent research with mitochondrial uncouplers - small ‘fat burning’ molecules that could be used to help treat NASH.
“The challenging thing about NASH is that there are a lot of patients who don’t even know that they have it because the diagnosis is so poor,” said Santos, who is an affiliated member of the Fralin Life Sciences Institute and the Virginia Tech Center for Drug Discovery. “Yes, the liver is a very malleable organ. But if you have a continuous, decades-long insult, and you don’t know that you have the disease, the damage will be irreversible.”
With the NIH grant, Santos will be able to take his prototype molecules that have already been developed and optimize them by synthesizing a lot of derivatives. After that, Santos will be able to put the various prototype molecules into animal models of disease. The grant will support a medicinal chemistry program, which will be composed of post-doctoral researchers, graduate students, and undergraduates at Virginia Tech.
In collaboration with Kyle Hoehn, an assistant professor of pharmacology from the University of Virginia and an associate professor of biotechnology and biomolecular sciences at the University of New South Wales in Australia, the team’s medicinal chemistry program will begin an iterative process of chemical synthesis and biological testing to produce effective, new drugs and studying their effect on the liver. Hoehn is an expert metabolic physiologist who will perform studies in cells and animal models.
A mitochondrial uncoupler is a small molecule that alters metabolism so that cells can burn off more fuel - no exercise needed. Santos has recently developed and tested novel compounds, but with this grant he will be able to improve their ability to act as drugs.
When mitochondrial uncouplers are ingested orally, they enter the digestive tract, are absorbed in the body and brought to the liver. Ensuring that the compounds work before being destroyed by the liver’s strict detoxification process is the tricky part.
When the liver is presented with a drug, it has to decide if the compound is foreign or not. Once the drug is absorbed into the liver, it needs sufficient time to perform the desired effect before being metabolized or excreted. Because of these factors, drug researchers work tirelessly to improve the drug’s half-life, or the length of time that a drug is effective in the body.
“Our goal here is not just to make mitochondrial uncouplers, but to make these mitochondrial uncouplers drug-like,” said Santos. “So that it will have a long half-life in the animal and have an effect that we desire.”
The team will test their drugs using a model where mice are fed a 36 week-long diet that is rich in fat and simulates NASH and its pathology. Although this work takes a long time, researchers hail it as the “gold standard” because it is a model that best mimics the human condition. Only the most promising of compounds will be investigated further.
The Santos and Hoehn labs hope to transition the anti-fat treatment from animal models to a treatment for NASH in humans.
Pathologists have developed a method of determining how severe the damage is. A pathologist will look at the liver slices from the biopsy and will give a score based on the amount of liver fat, ballooning, fibrosis, and inflammation.
“We are trying to help reverse some of the liver damage with the development of our mitochondrial uncouplers,” said Santos. “We will keep working until, hopefully, we get a good drug-like compound at the end of the day for human clinical trials.”
Seed funding for this project was received from Virginia Catalyst with matching funds from Santos and Hoehn’s biotech company Continuum Biosciences. The company aims to improve the ways in which our bodies burn fuel and fight back against our bodies ability to store excess nutrients as we age.
Their current NASH treatment compounds are licensed to Life Biosciences and are patented by Virginia Tech.
Written by Kendall Daniels