Researchers have identified a new compound that improves insulin and treated diabetes responses in obese mouse models.
Researchers have identified a novel compound that could serve as the basis for developing a new class of drugs to treat diabetes. The study was conducted at Ohio State University’s Wexner Medical Center and the College of Medicine in the United States.
According to the team, adenosine monophosphate-activated protein kinase (Ampk) is a key enzyme that is involved in recording the body’s energy stores in cells. Impairment of energy metabolism occurs in obesity, which is a risk factor for diabetes. Some drugs used to treat diabetes, such as metformin, make Ampk more active.
The researchers identified an orphan ubiquitin E3 ligase subunit protein called Fbxo48 that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation.
“In our study, we discovered a protein called Fbxo48 that is involved in removing Ampk from cells. We developed and tested a compound called BC1618 that blocks Fbxo48 and is much more effective than metformin at increasing Ampk function. BC1618 improved the response to insulin, a measure of the effectiveness of diabetes drugs, in obese mice, ”said Dr. Rama Mallampalli, lead author of the study.
The team showed that, consistent with increasing Ampk activity, BC1618 promoted mitochondrial cleavage, facilitated autophagy, and improved liver insulin sensitivity in obese mice.
“This study builds on our previous research to understand how critical proteins are removed or broken down in the body. The research team had previously designed and manufactured a family of anti-inflammatory drugs that have been approved by the US Food and Drug Administration (FDA) and are about to enter Phase I trials, ”Mallampalli said. “With this new connection as the backbone, our team, including Dr. Bill Chen and Dr. Yuan Liu of the University of Pittsburgh, will make other compounds that are more effective and safer in animal models, and then test them in animal models of diabetes. Ultimately, we want to get FDA approval for human testing. “
The study results are published online in the journal Nature Chemical Biology.
Drug development, drug discovery, drug derivations, drug targets, enzymes, protein, proteomics, research and development, target molecule, target validation, therapeutics