Enteropeptidase: A Gene Associated with a Starvation Human Phenotype and a Novel Target for Obesity Treatment (original) (raw)
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Current Pharmaceutical Biotechnology, 2014
Treatments of obesity and type II diabetes target often gene functions involved in appetite-satiety, fat and carbohydrate metabolism or thermogenesis. None of these, have provided efficient drug therapy due to a large number of genes involved in weight and energy management, the redundancy of biochemical pathways and the environmental factors. Here I discuss a new approach based on studies of genes/proteins that are associated with human "lean or starvation" phenotype that became very rare in the course of evolution. This approach has led to the identification of the congenital enteropeptidase deficiency gene and the Andersonʼs Disease gene as a potential targets for obesity and type II diabetes treatment. The advantages of these targets are: 1) they are expressed exclusively in the intestine; 2) they are peripheral targets as opposed to systemic targets; 3) they are not redundant targets. These targets open new hopes for the development of novel drugs for the treatment of common metabolic syndrome.
Targeting Enteropeptidase with Reversible Covalent Inhibitors To Achieve Metabolic Benefits
Journal of Pharmacology and Experimental Therapeutics, 2020
Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clinically for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clinical efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (k inact /K I) of 1.5 Â 10 4 M 21 s 21. High-resolution liquid chromatography-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 hours. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 Å, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptindeficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clinically relevant efficacy. SIGNIFICANCE STATEMENT Interest in targeted covalent drugs has expanded in recent years, particularly so for kinase targets, but also more broadly. This study demonstrates that reversible covalent inhibition of the serine protease enteropeptidase is a therapeutically viable approach to the treatment of metabolic diseases and that mechanistic details of inhibition are relevant to clinical efficacy. Our mechanistic and kinetic studies outline a framework for detailed inhibitor characterization that is proving essential in guiding discovery efforts in this area.
New Function for an Old Enzyme: NEP Deficient Mice Develop Late-Onset Obesity
PLoS ONE, 2010
Background: According to the World Health Organization (WHO) there is a pandemic of obesity with approximately 300 million people being obese. Typically, human obesity has a polygenetic causation. Neutral endopeptidase (NEP), also known as neprilysin, is considered to be one of the key enzymes in the metabolism of many active peptide hormones.
Centrally Acting Agents for Obesity: Past, Present, and Future
Drugs, 2018
For many years obesity was believed to be a condition of overeating that could be resolved through counseling and short term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long-term. This review of central nervous system (CNS) acting anti-obesity drugs evaluates current therapies such as phentermine/topiramate which act through multiple neurotransmitter pathways to reduce appetite. In the synergistic mechanism of bupropion/ naltrexone, naltrexone blocks the feedback inhibitory circuit of bupropion to give greater weight loss. Lorcaserin, a selective agonist of a serotonin receptor that regulates food intake, and the glucagon-like-peptide-1 (GLP-1) receptor agonist liraglutide are reviewed. Future drugs include tesofensine, a potent triple reuptake inhibitor in phase III trials for obesity and semaglutide, an oral GLP-1 analog approved for diabetes and currently in trials for obesity. Another potential new pharmacotherapy, setmelanotide, is a melanocortin-4 receptor agonist which is still in an early stage of development. As our understanding of the communication between the CNS, gut, adipose tissue, and other organs evolves, it is anticipated that obesity drug development will move toward new centrally acting combinations and then to drugs acting on peripheral target tissues.
Targets for Medical Therapy in Obesity
Digestive Diseases, 2012
Obesity has more than doubled since 1980 all over the world, and in the European perspective it does not seem to be better. Obesity-related diseases like diabetes, hypertension, coronary heart disease, stroke and hyperlipidemia are the main cause of mortality and morbidity in developed countries. These are the reasons for continuous search for efficient treatment of obesity. One of the options is medical therapy. Over history, many anti-obesity drugs were introduced and subsequently removed from the market due to various side effects. Unfortunately, there is still no ideal drug for the treatment of obesity, and the current ones are very strictly evaluated. The anti-obesity drug should target patients that have previously failed to lose weight with lifestyle interventions, with body mass index (BMI) ≥30, or those with BMI ≥27 plus concomitant obesity-related risk factors or diseases. The only drug currently approved in Europe is orlistat, a pancreatic lipase inhibitor. Sibutramine, a...
Drug Design, Development and Therapy, 2014
The prevalence of obesity has increased worldwide, and approximately 25%-35% of the adult population is obese in some countries. The excess of body fat is associated with adverse health consequences. Considering the limited efficacy of diet and exercise in the current obese population and the use of bariatric surgery only for morbid obesity, it appears that drug therapy is the only available method to address the problem on a large scale. Currently, pharmacological obesity treatment options are limited. However, new antiobesity drugs acting through central nervous system pathways or the peripheral adiposity signals and gastrointestinal tract are under clinical development. One of the most promising approaches is the use of peptides that influence the peripheral satiety signals and brain-gut axis such as GLP-1 analogs. However, considering that any antiobesity drug may affect one or several of the systems that control food intake and energy expenditure, it is unlikely that a single pharmacological agent will be effective as a striking obesity treatment. Thus, future strategies to treat obesity will need to be directed at sustainable weight loss to ensure maximal safety. This strategy will probably require the coadministration of medications that act through different mechanisms.
Anti-obesity drugs: a critical review of current therapies and future opportunities
Pharmacology & Therapeutics, 2001
The last 25 years have seen a great increase in the incidence of obesity, both in the Western world and in developing third world countries. Despite the seeming inexorable progression of this disease, there have been limited advances in the pharmacotherapy of this condition. Of the newest introductions to the obesity drug portfolio, orlistat, which acts to prevent dietary fat absorption, and sibutramine, which seems to affect both arms of the energy balance equation, were the first new chemical entities to be introduced for the treatment of obesity in 30 years. In this article, we review these and other agents available in various countries for the treatment of obesity. Perhaps more importantly, we have focussed on areas of potential productivity in the future. The huge recent increase in our knowledge in this area has largely stemmed from discovery research at the genomics level. Over the last 5 or so years, this impetus in obesity research has provided us with exciting new drug targets involved in the regulation of feeding behaviour and cellular mechanisms involved in energy expenditure. Compared with the last 25 years, the future offers more hope. D
The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits
Nature Reviews Endocrinology
Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.
Existing and prospective pathways for intervention in treatment of obesity in a novel way‒a review, 2018
Medical treatment of obesity is difficult as newer drugs get elucidated and may show promise but as they undergo phase trials some or other side effects appear. Initially sibutramine was used for some years and then abandoned in view of CVS side effects. Rimonabant an endocannabaninoid receptor antagonist showed great promise as far as its antiobesity properties were concerned but had to be abandoned in trial phase due to appearance of severe psychiatric side effects including suicidal effects. Now although Qsymia is approved but its use is with caution due to the effects of fetal side effects like oral cleft lip, palate and propensity for CVS side effects. Similarly lorcarserin has now been categorized as schedule IV drug in view of it causing tumor development. Tesofensine has started showing severe side effects in initial phases of phase trials. The only drug approved is orlistat for long term obesity treatment. Antidiuretic drugs like GLP1R agonists like liraglutide are other drugs of promise. Newer discoveries resulting from genetic studies of obesity and MS have identified novel molecules which act on hunger and satiety peptidergic signaling of the gut-hypothalamic axis like ghrelin, PYY, NPY or the melanocortin system of the brain and are promising targets for future drug development. Thus the aim is to initiate drug development which not only treats obesity but also has a favorable impact on associated traits.