“Metabolism” describes the body’s chemical changes that create the necessary materials for growth and overall health. Metabolites are the substances made and used during these metabolic processes — or, as a new discovery from Scripps Research and its drug development arm, Calibr, points out, they could also be potent molecules for treating serious diseases.
In a study by metabolites published in August 2022, the researchers used new drug discovery technologies to discover a metabolite that converts white fat cells (“bad” fat) into brown fat cells (“good” fat cells). This discovery offers a potential way to address metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease. In fact, it speaks to the promise of using this creative drug discovery method to identify countless other potential therapies.
“The reason many types of molecules don’t make it to the market is because of toxicity,” said co-senior author Gary Siuzdak, Ph.D., the senior director of the Scripps Center for Metabolomics and professor of Chemistry, Molecular, and Computational Biology at Scripps Research. “With our technology, we can extract endogenous metabolites – that is, the ones the body makes itself – that can have the same impact as a drug with fewer side effects. The potential of this approach is even proven by the recent FDA approval of Relyvrio , the combination of two endogenous metabolites for the treatment of amyotrophic lateral sclerosis (ALS).”
Metabolic diseases are often caused by an imbalance in energy homeostasis, in other words, when the body takes in more energy than it uses. This is why certain therapeutic approaches focus on converting white fat cells (known as adipocytes) into brown fat cells. White adipocytes store excess energy and can eventually lead to metabolic diseases such as obesity, while brown adipocytes dissolve this stored energy into heat, ultimately increasing the body’s energy expenditure and bringing it back into balance.
To discover a therapy that could boost brown fat cell production, the researchers searched Calibr’s ReFRAME drug reuse collection — a library of 14,000 known drug compounds that have been approved by the FDA for other diseases or have been extensively tested on human subjects. safety. Using high-throughput screening — an automated drug discovery method for searching through large amounts of information — the scientists scanned ReFRAME for a drug with these specific capabilities.
This is how they discovered zafirlukast, an FDA-approved drug used to treat asthma. Through a series of cell culture experiments, they found that zafirlukast could turn adipocyte precursor cells (known as preadipocytes) into predominantly brown adipocytes, as well as convert white adipocytes into brown adipocytes.
While an encouraging finding, zafirlukast is toxic when given in higher doses, and it wasn’t fully understood how zafirlukast converts fat cells. This is when the researchers teamed up with Siuzdak and his team of metabolite experts.
“We had to use additional tools to break down the chemicals in the mechanism of zafirlukast,” said Kristen Johnson, Ph.D., co-senior author of the paper and director of Translational Drug Discovery Research at Calibr. “Putting another way, can we find a metabolite that had the same functional effect as zafirlukast, but without the side effects?”
Siuzdak and his team designed a new set of experiments known as drug-initiated activity metabolomics (DIAM) screening to help answer Johnson’s question. DIAM uses technologies such as liquid chromatography (a tool that separates components in a mixture) and mass spectrometry (an analytical technique that separates particles by weight and charge) to pool thousands of molecules and identify specific metabolites. In this case, the researchers looked in adipose tissue for metabolites that could lead to the production of brown fat cells.
After reducing 30,000 metabolic markers to just 17 metabolites, they found myristoylglycine – an endogenous metabolite that led to the production of brown adipocytes, without harming the cell. Of the thousands of metabolic features measured in the analysis, only myristoylglycine had this special property, even among nearly structurally identical metabolites.
“Identifying myristoylglycine among thousands of other molecules is testament to the strength of Siuzdak’s approach and these technologies,” Johnson added. “Our findings illustrate what happens when an analytical chemistry team and a drug discovery group work closely together.”
Carlos Guijas et al, Drug-Initiated Activity Metabolomics identifies myristoylglycine as a potent endogenous metabolite for human brown fat differentiation, metabolites (2022). DOI: 10.3390/metabo12080749
Quote: Drug Discovery Method Identifies Naturally Occurring Metabolite That Converts ‘Bad’ Fat to ‘Good’ Fat (2022, Oct. 13) Retrieved Oct. 13, 2022 from https://phys.org/news/2022-10-drug-discovery-method-natural -metabolite.html
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