Enteropeptidase: A Gene Associated with a Starvation Human Phenotype and a Novel Target for Obesity Treatment

Abstract

BackgroundObesity research focuses essentially on gene targets associated with the obese phenotype. None of these targets have yet provided a viable drug therapy. Focusing instead on genes that are involved in energy absorption and that are associated with a “human starvation phenotype”, we have identified enteropeptidase (EP), a gene associated with congenital enteropeptidase deficiency, as a novel target for obesity treatment. The advantages of this target are that the gene is expressed exclusively in the brush border of the intestine; it is peripheral and not redundant.Methodology/Principal FindingsPotent and selective EP inhibitors were designed around a boroarginine or borolysine motif. Oral administration of these compounds to mice restricted the bioavailability of dietary energy, and in a long-term treatment it significantly diminished the rate of increase in body weight, despite ad libitum food intake. No adverse reactions of the type seen with lipase inhibitors, such as diarrhea or steatorrhea, were observed. This validates EP as a novel, druggable target for obesity treatment.Conclusions In vivo testing of novel boroarginine or borolysine-based EP inhibitors validates a novel approach to the treatment of obesity.

Changes in the salivary protein profile of morbidly obese women either previously subjected to bariatric surgery or not

“…This protease has been identified as a constituent of human saliva which has a role to play in histatin proteolysis [43]. Although it is associated with the human phenotype linked to starvation [3], its role in the composition of saliva is not well understood. Zinc-α-2 glycoprotein presented higher values only in obese individuals who had not been subjected to bariatric surgery.…”

Discovery and characterization of a small‐molecule enteropeptidase inhibitor, SCO‐792

“…7,8 Interestingly, a recent seminal study suggested that inhibiting gut enteropeptidase may be a novel strategy for correcting obesity. 9 Concomitantly, accumulating reports suggest that the strong connection of plasma amino acid change with obesity and insulin resistance. 10 Considering that enteropeptidase is an upstream key molecule in a protein degradation process, 5 identifying potent and effective new enteropeptidase inhibitors and determining their biological actions in health and disease statuses are of great interest.…”

“…Congenital enteropeptidase deficiency in humans has resulted in intestinal malabsorption and a lean phenotype, which suggest the pivotal role of this enzyme in regulating body homeostasis . Interestingly, a recent seminal study suggested that inhibiting gut enteropeptidase may be a novel strategy for correcting obesity . Concomitantly, accumulating reports suggest that the strong connection of plasma amino acid change with obesity and insulin resistance .…”

New Perspectives on the Development of Antiobesity Drugs

“…This enzyme is present in the brush border of the intestine. Evidence: low MW inhibitors [174] Lipin-1: this is an enzyme present in brown adipose tissue. Evidence: KO mice [175] Melatonin: this hormone plays a role in appetite regulation: Evidence: phenotypic assay (zebrafish) [176] FTO: this is an N-methyl nucleic acid demethylase.…”