Discovery and development of gastrointestinal lipase inhibitors

Last updated
Lipase inhibitor
Drug class
Orlistat with greek symbol to explain side groups.jpg
Chemical structure of the lipase inhibitor Orlistat [1]
Class identifiers
ATC code A08AB
Mode of action Inhibits gastric lipase and pancreatic lipase
Legal status
In Wikidata

Lipase inhibitors belong to a drug class that is used as an antiobesity agent. Their mode of action is to inhibit gastric and pancreatic lipases, enzymes that play an important role in the digestion of dietary fat. [2] Lipase inhibitors are classified in the ATC-classification system as A08AB (peripherally acting antiobesity products). [3] Numerous compounds have been either isolated from nature, semi-synthesized, or fully synthesized and then screened for their lipase inhibitory activity [4] but the only lipase inhibitor on the market (October 2016) is orlistat (Xenical, Alli). [5] Lipase inhibitors have also shown anticancer activity, by inhibiting fatty acid synthase. [6]

Contents

Discovery of lipase inhibitors and their development

Pancreatic lipase inhibitor was originally discovered and isolated from fermented broth of the Streptomyces toxytricini bacterium in 1981 and named lipstatin. [7] It is a selective and potent irreversible inhibitor of human gastric and pancreatic lipases. Tetrahydrolipstatin, more commonly known as orlistat, is a saturated derivative produced by hydrogenation. It was developed in 1983 by Hoffmann-La Roche and is a more simple and stable compound than lipstatin. [5] [8] [9] For that reason orlistat was chosen over lipstatin for development as an anti-obesity drug. [1] [10] It is the only available FDA-approved oral lipase inhibitor and is known on the market as Xenical and Alli. [5] Initially orlistat was developed as a treatment for dyslipidemia, not as an anti-obesity agent. When researchers found out that it promotes less energy uptake, the focus was switched to obesity. [11]

Orlistat has a few adverse effects. Most reported side effects are gastrointestinal; including liquid stools, steatorrhea and abdominal pain. More severe and serious are interactions between orlistat and anticoagulants when given in combination. It can increase INR which can lead to insufficient anticoagulant treatment and bleeding. [12] These adverse effects of orlistat are more common early in the therapy but usually decrease with time. Pancreatic lipases do not only affect the hydrolysis of triglycerides but are also necessary for hydrolysis of fat soluble vitamins. Due to this, the absorption of fat-soluble vitamins may decrease. Therefore, it is recommended to take a multiple-vitamin supplement during orlistat therapy. [9] [12]

Cetilistat, a new lipase inhibitor, is an experimental drug for obesity. In October 2016 the drug was still in clinical trials. [13] Cetilistat was developed to overcome the adverse effects on the gastrointestinal tract of orlistat. It has a different structure but similar inhibition activity to the gastrointestinal lipase. However cetilistat interacts differently with the fat micelles from digested food, therefore it has less side effects and better tolerability. [14]

Mechanism of action

Figure 1: During fat digestion, lipases in the gastrointestinal tract hydrolyse fat (triglycerides) into smaller molecules (free fatty acids and monoglycerides) which can be absorbed through the duodenal mucosa. Lipase inhibitors bind to lipases and inactivate the enzyme. That leads to excretion of the undigested fat with faeces. Lipase and lipase inhibitor mechanism of action in fat digestion.png
Figure 1: During fat digestion, lipases in the gastrointestinal tract hydrolyse fat (triglycerides) into smaller molecules (free fatty acids and monoglycerides) which can be absorbed through the duodenal mucosa. Lipase inhibitors bind to lipases and inactivate the enzyme. That leads to excretion of the undigested fat with faeces.

The lipase inhibitors lipstatin and orlistat act locally in the intestinal tract. They are minimally absorbed in the circulation because of their lipophilicity. [7] Hence, they do not affect systemic lipases. [11]

The mechanism of lipase inhibitors in fat digestion is shown in figure 1. These inhibitors bind covalently as an ester to the serine hydroxyl group at the active site on pancreatic- and gastric lipases and form a stable complex. [7] [15] This results in a conformational change in the enzyme which causes exposing of the catalytic active site. When the active site is exposed, the hydroxyl group on the serine residue is acylated. This leads to irreversible inactivation of the enzyme. The inactive lipase is incapable of hydrolysing fats into absorbable fatty acids and monoglycerides, therefore triglycerides are excreted undigested with faeces.[ citation needed ] With this mode of action calorie uptake from fat in food is limited, hence body weight is reduced. [16] [17] The main role of lipase inhibitors is therefore to inhibit lipases in the gastrointestinal tract, but they do not have significant activity against proteases, amylases or other digestive enzymes. [11]

Cetilistat has a bicyclic structure but lacks the β-lactone ring. It acts in a similar way as a typical lipase inhibitor that has the β-lactone structure. [4] [16]

Drug target

Lipases in the gastrointestinal tract play a critical role in fat digestion. More than 95% of fat in food consists of triglycerides, which are categorized based on the length of fatty acids connected to glyceride backbone. [18] The length of long-chain triglycerides prevent their absorption through the intestinal mucosa. [19] For that reason lipases in the gastrointestinal tract must hydrolyse it to smaller molecules, free fatty acids and monoglyceride, [20] before absorption can occur. [21]

Gastric lipase

Gastric- and lingual lipases are the two acidic lipolytic enzymes that origin preduodenal but the gastric lipase is in much higher levels in humans. Gastric lipase is synthesized and secreted from gastric chief cells in the stomach and is stable at pH 1,5-8, [21] but has maximum activity at pH 3-6. [20] Fat digestion begins when gastric lipase hydrolyses dietary triglycerides, by cleaving only one long-, medium- or short-acyl chain from the glyceride backbone and release free fatty acids and diacylglycerols. The enzyme hydrolyses esters at position sn-3, the acyl chain at the bottom, more rapidly than esters at sn-1 position, the acyl chain on the top of the glyceride backbone. However the gastric lipase activity against phospholipids and cholesterol esters is poor.

Gastric lipase is composed of 379 amino acids. Fully glycosylated protein is 50kDa and unglycosylated enzyme is 43kDa. However deglycosylation of the enzyme does not affect the activity of the enzyme. [21] The hydrophobic region around Ser152, which has the hexapeptide sequence Val-Gly-His-Ser-Gln-Gly, is essential for the catalytic activity of gastric lipase. At the N-terminal, Lys4 is necessary for the enzyme to bind at lipid-water interfaces. [21]

Figure 2: The pancreatic lipase consists of two domains. The small C-terminal domain takes part in colipase binding and the large N-terminal has the catalytic site. 1lpa opm.png
Figure 2: The pancreatic lipase consists of two domains. The small C-terminal domain takes part in colipase binding and the large N-terminal has the catalytic site.

Pancreatic lipase

Pancreatic lipase is the most important lipolytic enzyme in the gastrointestinal tract [21] and is essential for fat digestion. [23] Pancreatic lipase is secreted from acinar cells in the pancreas [24] and its secretion, with the pancreatic juice to the small intestine, is stimulated by hormones. These hormones are induced in the stomach by hydrolysed products in gastric digestion. [25] [26] The pancreatic lipase is secreted to the small intestine where it is most active, at pH 7-7,5. [20] Pancreatic lipase hydrolyses triglycerides and diglycerides by cleaving acyl chains at the sn-1 and sn-3 position [21] and releases free fatty acids and 2-monoglycerides. [23]

The pancreatic lipase consists of 465 amino acids. Schematic picture of pancreatic lipase is shown in figure 2. Pancreatic and gastric lipases share little homology but have the same hydrophobic region at the active site, which is important for the lipolytic activity. The hydrophobic region has the hexapeptide sequence Val-Gly-His-Ser-Gln-Gly and is at Ser153 in pancreatic lipases but Ser152 in gastric lipases. [21]

Chemistry of lipase inhibitors

β-lactone class

The chemical structure of compounds play an important role in binding to their target. The most important and necessary chemical group for the binding and activity of these compounds is the β-lactone (beta-lactone) ring which is the central pharmacophore. The β-lactone moiety is shown in red in the structures in the table below. Researches have shown that cleavage of the β-lactone ring results in loss of inhibitory activity of the inhibitors, which makes the β-lactone structure a crucial part in biological activity. [5] [8] The lactone ring structure binds irreversibly to the active site of the lipase and forms covalent bond, which leads to inhibition. [27]

Drugs of this class include:

Structure-activity relationship (SAR)

Most natural lipase inhibitors differ only in the structure of the side chains and the nature of the linked amino acids, but have the same β-lactone ring [5] in (S)-configuration as a primary structure. [1] Besides the role of the β-lactone ring in structure-activity relationship, the nature of the functional groups (e.g. ester or ether and the chain length at the β-site) also matter. [4] However a trans-position of the side-chains on the β-lactone ring is crucial for its activity. [31]

Lipase inhibitors bearing a β-lactone ring
LipstatinOrlistatEsterastinValilactonePanclicin DEbelactone Vibralactone
Structure
Structure of lipstatin with B-lactone market red to show common structure in various of compound.jpg
Structure of orlistat with B-lactone market red to show common structure in various of compound.jpg
Structure of esterastin with B-lactone market red to show common structure in various of compound.jpg
Structure of valilactone with B-lactone market red to show common structure in various of compound.jpg
Structure of panclicin B with B-lactone market red to show common structure in various of compound.jpg
Structure of ebelactone B with B-lactone market red to show common structure in various of compound.jpg
Structure of vibralactone with B-lactone market red to show common structure in various of compound.jpg
IC50 value6.9 × 10−2 μg/ml [1] 1.2 × 10−1 μg/ml [1] 2.0 × 10−1 μg/ml [1] 1.4 × 10−4 μg/ml [1] 3.9 × 10−1 μg/ml [1] 1.0 × 10−3 μg/ml [1] 4.0 × 10−1 μg/ml [1]

Synthetic lipase inhibitor: cetilistat

Cetilistat
Structure Cetilistat.png
IUPAC2-hexadecoxy-6-methyl-3,1-benzoxazin-4-one [32]
Chemical formulaC25H39NO3 [32]
Molar mass (g/mol)401.6 [32]
IC505.95 nmol/l = 2.39 × 10−3 μg/mL (human pancreatic lipase) [33]

Cetilistat is a synthetic lipase inhibitor. Instead of having a β-lactone structure like most of the lipase inhibitors, [16] it has a bicyclic benzoxazinone ring. It is also a lipophilic compound but differs in the hydro- and lipophilic side chain. [14] The structure and more information about Cetilistat is shown in the table on the right. [32]

Other lipase inhibitors

Other lipase inhibitors have been recognized, e.g. from different plant products. These include alkaloids, carotenoids, glycosides, polyphenols, polysaccharides, saponins and terpenoids. However, none of these have been used clinically as lipase inhibitors. More active lipase inhibitors are the lipophilic compounds from microbial sources. [4]

Lipase inhibitors from microbial source can be divided into two classes based on their structure. Those who have a β-lactone ring are lipstatin, valilactone, percyquinin, panclicin A-E, ebelactone A and B, vibralactone and esterastin. Those who do not have a β-lactone ring are (E)-4-amino styryl acetate, ε–polylysine and caulerpenyne. [8]

Lipase inhibitors have also been made synthetically, e.g. cetilistat, based on the structure of triglycerides and other natural lipase substrates. [8] However, the synthetic lipase inhibitors differ in structure and some of them lack the β-lactone ring. [4]

Additional activities

Potential for cancer treatment

As further discussed, orlistat is a pancreatic and gastric lipase inhibitor. Orlistat is also a potent thioesterase inhibitor and therefore inhibits fatty acid synthase (FAS). Since FAS is essential for tumor cells, for its growth and survival, and is upregulated and overexpressed in variety of tumors, [34] scientists have high expectations for FAS as an oncology drug target. [35] Orlistat inhibits FAS with the same mechanism as it does with pancreatic lipase, that is by binding covalently to the active serine site. [35] This effect of orlistat as a FAS-inhibitor was first identified in a high throughput screening for enzymes with prostate cancer inhibition activity. However FAS is resistant to many cancer medicines. Orlistat sensitizes these FAS resistance cancer drugs, by inhibiting FAS. [36] There is a low FAS expression in normal tissues so the activity of orlistat on normal cells is limited. Because of the difference in FAS expression between normal cells and cancer cells, orlistat selectively targets tumor cells. Due to this FAS is a potential drug target in cancer therapy. [34] [37]

Orlistat works locally in the intestines as a lipase inhibitor, and therefore suffers from several limitations in its development as a systemic drug. Its poor bioavailability and solubility are the main reasons to develop a new anticancer analogue to overcome these limitations. [6] [34]

Related Research Articles

<span class="mw-page-title-main">Small intestine</span> Organ in the gastrointestinal tract

The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the pancreatic duct to aid in digestion. The small intestine is about 5.5 metres long and folds many times to fit in the abdomen. Although it is longer than the large intestine, it is called the small intestine because it is narrower in diameter.

Digestion is the breakdown of large insoluble food compounds into small water-soluble components so that they can be absorbed into the blood plasma. In certain organisms, these smaller substances are absorbed through the small intestine into the blood stream. Digestion is a form of catabolism that is often divided into two processes based on how food is broken down: mechanical and chemical digestion. The term mechanical digestion refers to the physical breakdown of large pieces of food into smaller pieces which can subsequently be accessed by digestive enzymes. Mechanical digestion takes place in the mouth through mastication and in the small intestine through segmentation contractions. In chemical digestion, enzymes break down food into the small compounds that the body can use.

<span class="mw-page-title-main">Orlistat</span> Drug designed to treat obesity

Orlistat, sold under the brand name Xenical among others, is a medication used to treat obesity. Its primary function is preventing the absorption of fats from the human diet by acting as a lipase inhibitor, thereby reducing caloric intake. It is intended for use in conjunction with a healthcare provider-supervised reduced-calorie diet.

<span class="mw-page-title-main">Malabsorption</span> Abnormality in absorption of food nutrients across the gastrointestinal tract

Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety of anaemias.

Steatorrhea is the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may occur. There is increased fat excretion, which can be measured by determining the fecal fat level.

<span class="mw-page-title-main">Digestive enzyme</span> Class of enzymes

Digestive enzymes take part in the chemical process of digestion, which follows the mechanical process of digestion. Food consists of macromolecules of proteins, carbohydrates, and fats that need to be broken down chemically by digestive enzymes in the mouth, stomach, pancreas, and duodenum, before being able to be absorbed into the bloodstream. Initial breakdown is achieved by chewing (mastication) and the use of digestive enzymes of saliva. Once in the stomach further mechanical churning takes place mixing the food with secreted gastric acid. Digestive gastric enzymes take part in some of the chemical process needed for absorption. Most of the enzymatic activity, and hence absorption takes place in the duodenum.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

<span class="mw-page-title-main">Lingual lipase</span> Mammalian protein found in Homo sapiens

Lingual lipase is a member of a family of digestive enzymes called triacylglycerol lipases, EC 3.1.1.3, that use the catalytic triad of aspartate, histidine, and serine to hydrolyze medium and long-chain triglycerides into partial glycerides and free fatty acids. The enzyme, released into the mouth along with the saliva, catalyzes the first reaction in the digestion of dietary lipid, with diglycerides being the primary reaction product. However, due to the unique characteristics of lingual lipase, including a pH optimum 4.5–5.4 and its ability to catalyze reactions without bile salts, the lipolytic activity continues through to the stomach. Enzyme release is signaled by autonomic nervous system after ingestion, at which time the serous glands under the circumvallate and foliate lingual papillae on the surface of the tongue secrete lingual lipase to the grooves of the circumvallate and foliate papillae, co-localized with fat taste receptors. The hydrolysis of the dietary fats is essential for fat absorption by the small intestine, as long chain triacylglycerides cannot be absorbed, and as much as 30% of fat is hydrolyzed within 1 to 20 minutes of ingestion by lingual lipase alone.

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

Fatty acid synthase (FAS) is an enzyme that in humans is encoded by the FASN gene.

<span class="mw-page-title-main">Lipstatin</span> Chemical compound

Lipstatin is a potent, irreversible inhibitor of pancreatic lipase. It is a natural product that was first isolated from the actinobacterium Streptomyces toxytricini.

<span class="mw-page-title-main">Beta-ketoacyl-ACP synthase</span> Enzyme

In molecular biology, Beta-ketoacyl-ACP synthase EC 2.3.1.41, is an enzyme involved in fatty acid synthesis. It typically uses malonyl-CoA as a carbon source to elongate ACP-bound acyl species, resulting in the formation of ACP-bound β-ketoacyl species such as acetoacetyl-ACP.

<span class="mw-page-title-main">Gastric lipase</span> Class of enzymes

Gastric lipase, also known as LIPF, is an enzymatic protein that, in humans, is encoded by the LIPF gene.

<span class="mw-page-title-main">Adipose triglyceride lipase</span> Mammalian protein found in Homo sapiens

Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.

<span class="mw-page-title-main">Pancreatic lipase family</span> Mammalian protein found in Homo sapiens

Triglyceride lipases are a family of lipolytic enzymes that hydrolyse ester linkages of triglycerides. Lipases are widely distributed in animals, plants and prokaryotes.

<span class="mw-page-title-main">Antinutrient</span> Compound that affects the absorption of nutrients

Antinutrients are natural or synthetic compounds that interfere with the absorption of nutrients. Nutrition studies focus on antinutrients commonly found in food sources and beverages. Antinutrients may take the form of drugs, chemicals that naturally occur in food sources, proteins, or overconsumption of nutrients themselves. Antinutrients may act by binding to vitamins and minerals, preventing their uptake, or inhibiting enzymes.

Cetilistat is a drug designed to treat obesity. It acts in the same way as the older drug orlistat (Xenical) by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.

<span class="mw-page-title-main">Lipase</span> Class of enzymes which cleave fats via hydrolysis

In biochemistry, lipase refers to a class of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually treated separately from "conventional" lipases. Unlike esterases, which function in water, lipases "are activated only when adsorbed to an oil–water interface". Lipases perform essential roles in digestion, transport and processing of dietary lipids in most, if not all, organisms.

<span class="mw-page-title-main">Lipase inhibitors</span>

Lipase inhibitors are substances used to reduce the activity of lipases found in the intestine. Lipases are secreted by the pancreas when fat is present. The primary role of lipase inhibitors is to decrease the gastrointestinal absorption of fats. Fats then tend to be excreted in feces rather than being absorbed to be used as a source of caloric energy, and this can result in weight loss in individuals. These inhibitors could be used for the treatment of obesity, which can subsequently lead to Type 2 diabetes and cardiovascular diseases if not managed. An example of a lipase inhibitor is orlistat.

<span class="mw-page-title-main">Human digestive system</span> Digestive system in humans

The human digestive system consists of the gastrointestinal tract plus the accessory organs of digestion. Digestion involves the breakdown of food into smaller and smaller components, until they can be absorbed and assimilated into the body. The process of digestion has three stages: the cephalic phase, the gastric phase, and the intestinal phase.

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