Calpain is a cytosolic proteinase that regulates of a wide range of physiological functions. The enzyme has been implicated in various pathological conditions including neurodegenerative disorders, ...cardiovascular disorders, cancer, and several other diseases. Therefore, calpain inhibitors are of interest as therapeutic agents and have been studied in preclinical models of several diseases in which the enzyme has been implicated.
Calpain inhibitors that were disclosed over the last 5 years (2015-2019) include calpastatin-based peptidomimetics; thalassospiramide lipopeptides; disulfide analogs of alpha-mercaptoacrylic acids; allosteric modulators; azoloimidazolidenones; and macrocyclic/non-macrocyclic carboxamides. The effectiveness of some of the inhibitors in preclinical animal models is discussed.
Significant milestones that were made over this time frame include: a) disclosure of novel blood-brain barrier (BBB) permeable calpastatin analogs as calpain inhibitors; b) disclosure that potent calpain inhibitors can be obtained by targeting the hydrophobic pockets on chain A of PEF(S) of the small subunit of calpain; c) use of PEF(S) (PDB ID: 4WQ2) in virtual screening to identify novel structurally diverse calpain inhibitors; and d) mitigation of the metabolic instability of the alpha-ketoamide warhead of calpain inhibitors.
A Survey of Calpain Inhibitors DONKOR, I. O
Current medicinal chemistry,
12/2000, Letnik:
7, Številka:
12
Journal Article
Recenzirano
Calpain is unique among the cysteine protease family of enzymes in that it combines thiol protease activity with calmodulin-like activity. Despite its wide spread distribution the exact physiological ...function(s) of calpain is yet to be deciphered. The enzyme is however, implicated in a number of pathophysiological conditions. Due to the potential of calpain as a therapeutic target a number of inhibitors have been described for the enzyme. In this article we have grouped calpain inhibitors into those derived from natural sources, and those derived from chemical synthesis. Additionally, an overview of functional groups that have been used as "warheadso of calpain inhibitors is presented along with a discussion of the structure activity relationship studies of the address region of peptidyl calpain inhibitors. Recent work in this area has led to a better understanding of the structural requirements for tight binding of inhibitors to the active site of calpain. A discussion of peptidomimetic calpain inhibitors, nonpeptide calpain inhibitors, and selectivity of some calpain inhibitors are also presented. The recent disclosure of the crystal structure of a nonpeptide calpain inhibitor bound to a hydrophobic pocket on the calcium-binding domain of calpain has opened the door to future development of potent cell permeable nonpeptide calpain inhibitors.
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•The benefits of alkali pre-treatment and bioaugmentation are discussed.•An integrated cascading system is proposed to increase grass biomethane production.•The modelled integrated ...system potentially increases biomethane production by 47%.
Anaerobic digestion (AD) is a bioprocess technology that integrates into circular economy systems, which produce renewable energy and biofertilizer whilst reducing greenhouse gas emissions. However, improvements in biogas production efficiency are needed in dealing with lignocellulosic biomass. The state-of-the-art of AD technology is discussed, with emphasis on feedstock digestibility and operational difficulty. Solutions to these challenges including for pre-treatment and bioaugmentation are reviewed. This article proposes an innovative integrated system combining alkali pre-treatment, temperature-phased AD and bioaugmentation techniques. The integrated system as modelled has a targeted potential to achieve a biodegradability index of 90% while increasing methane production by 47% compared to conventional AD. The methane productivity may also be improved by a target reduction in retention time from 30 to 20 days. This, if realized has the potential to lower energy production cost and the levelized cost of abatement to facilitate an increased resource of sustainable commercially viable biomethane.
The release of angiotensin converting enzyme inhibitory (ACE-I), antioxidant and immunomodulatory peptides from milk proteins by selected Lactobacillus helveticus strains and their crude protease ...extracts (CPE) was investigated. Reconstituted skim milk (RSM) was incubated with L. helveticus strains or CPE and samples were tested for functionality using a human peripheral blood mononuclear cell model. Milk peptides produced by L. helveticus 474 CPE with ACE-I activity increased significantly after 6 h incubation followed by a significant reduction after 12 h. Peptides formed by CPE of L. helveticus 1188 showed a significantly greater antioxidative capacity than those from other strains. These peptides also differentially stimulated human peripheral blood mononuclear cells with those liberated by L. helveticus 1188 CPE inducing the highest production of interleukin-10, whereas the CPE of L. helveticus 474 formed peptides with significant induction of interferon-γ. These strains might potentially be used in the development of functional fermented food products.
Introduction:
Calpain is a family of cysteine proteases found in eukaryotes and a few bacteria. There is considerable interest in the search for calpain inhibitors because the enzyme has been ...implicated in several diseases including ocular disorders, neurodegenerative disorders, metabolic disorders and cancer.
Areas covered:
An overview of calpain inhibitors disclosed between 2012 and 2014 is presented. Among these are epoxysuccinates, dipeptide imaging agents, macrocyclic inhibitors, α-helical peptidomimetic inhibitors, carboxamides, 5-azolones and α-mercaptoacrylates. Additionally, preclinical studies of calpain inhibitors in pathologies such blood disorders, ocular disorders, neurological disorders and muscle disorders are discussed.
Expert opinion:
Major advances made in calpain inhibitor research between 2012 and 2014 include: i) the discovery of cytosolic-stable carboxamide calpain inhibitors; ii) synthesis of epoxysuccinates with excellent bioavailability; iii) disclosure of the X-ray crystal structures of novel α-mercaptoacrylates bound to the pentaEF hand region from human calpain; and iv) disclosure of calpain inhibitors as anti-sickling agents. Several calpain inhibitors were reported but limited effort was directed towards the discovery of calpain isoform selective agents, which continues to dampen the therapeutic potential of calpain inhibitors.
As a major cause of death, cancer has affected the world population, both directly and indirectly. There are however, growing numbers of cancer cases some of which could be prevented or even treated ...using natural compounds. Bioactive peptides from terrestrial and marine environment have been claimed to potentially reduce the risk of chronic diseases or maintain health. Fish processing industry produces more than 50% by-products which can be converted into valuable fish protein hydrolysate (FPH) by chemical or biochemical hydrolysis. This paper discusses the potency of fish by-products as sources of bioactive peptides with anticarcinogenic potential. Moreover, a short review about the antioxidant and anticancer activities of novel bioactive peptides isolated from fish by-products is presented.
Underutilised Australian Eastern School Whiting (Sillago flindersi) fish was investigated for in-vitro bioactivities, after exposure to fish endogenous and gastrointestinal (pepsin and pancreatin) ...enzymes. The study comprised of storing fish at chilled (4 and 6°C) and freezing (-18°C) temperatures for 7 and 28 days, respectively. Hydrolysis by endogenous enzymes only, resulted in increased bioactivities for the 4°C samples, whereas significant decreases (p < 0.05) were observed for the 6 and -18°C samples. However, bioactivities of these samples increased significantly (p < 0.05) after further hydrolysis under simulated digestion conditions. Proteolysis by digestive enzymes, mainly pancreatin considerably enhanced the antioxidant activities. To benefit from the health properties of eastern school whiting fish, it is suggested to consume the fish fresh. The intent is to enhance full use of fish and not certain parts such as fish oil. For proper utilization and sustainability, whole fish must be used.
► Proteolytic activity of studied enzymes was species dependent. ► Silver trevally demonstrated the highest calpain-like activity. ► Barracouta exhibited the highest endogenous activity of cathepsins ...B, D, H, and L. ► Cathepsins B and B+L activities were higher than cathepsin H in studied species.
The hydrolytic activity of major endogenous proteases, responsible for proteolysis of myofibrillar proteins during post-mortem storage, may be an indicator of the textural quality of fish which influences consumer purchasing behaviour and thus market value of the final product. Furthermore, it may also influence the type and bioactive properties of the peptides released during post-mortem proteolysis of myofibrillar proteins. This study compared the activities of cathepsins B, B+L, D, H and calpain-like enzymes in crude muscle extracted from 16 Australian underutilized fish species. Fish species had a significant effect on the activity of these enzymes with barracouta showing the highest cathepsins B, B+L, D and H activities. Activities of cathepsins B and B+L were higher than cathepsin H for all studied species. The more commercially important rock ling and tiger flathead demonstrated higher cathepsin B+L activity, whereas gemfish and eastern school whiting showed higher activity towards cathepsin B. Underutilized fish species showing higher endogenous protease activities may be suitable for fish sauce production, whereas those with lower protease activities for surimi processing.
Short-chain fatty acids (SCFAs) acetate, propionate, butyrate and lactate were determined in 12 % reconstituted skim milk (RSM) and RSM supplemented with inulin (RSMI). The fermentation was performed ...with
Bifidobacterium animalis
subsp.
lactis
(BB 12) and
Lactobacillus rhamnosus
LGG ATCC 53013. Fermentation culture activities produced substantial amounts of SCFAs, which were detected and quantitated using a HPLC-UV technique. Using HPLC-UV, we were able to detect low concentrations of lactate and SCFAs from fermented samples; lactate, acetate, propionate and butyrate were detected at 10.10, 12.06, 14.80 and 18.06 μg/mL, respectively. The retention time of all SCFAs and lactic acid were similar to the standard quality control (±0.05), and average recovery ranged between 89.73 and 91.03 %. The experimental conditions and sample preparation were applied to preparative HPLC to isolate and purify SCFAs with concentration range between 0.09 and 2.86 mg/mL. The purity of extracted SCFAs was confirmed using atmospheric pressure chemical ionization/mass spectrometry by determining the molecular masses of target purified compounds. The scaled up validated analytical HPLC-UV method will further enhance and improve the use of this approach to produce purified large-scale SCFAs.
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The calpains are a conserved family of cysteine proteases that includes several isoforms of which µ–calpain and m-calpain are the most widely distributed in mammalian cells. Calpains ...have been implicated in normal physiological processes as well as cellular abnormalities such as neurodegenerative disorders, cataract, and cancer. Therefore, calpain inhibitors are of interest as potential therapeutic agents. We have synthesized four new sulfonamide-based peptidomimetic compounds 2–5 as inhibitors of μ-calpain that incorporate (E)-1-(phenyl)-2-phenyldiazene and (E)-1-(phenyl)-2-phenylethene functionalities as the N-terminal capping groups of the inhibitors. Compound 5 with Ki value of 9 nM versus μ-calpain was the most potent member of the group. The compounds were predicted to be more lipophilic compared to MDL28170 based on CLogP estimation. They displayed moderate to good antiproliferative activity versus melanoma cell lines (A-375 and B-16F1) and PC-3 prostate cancer cells in vitro. Additionally, one member of the group (compound 3) inhibited DU-145 cell invasion by 80% at 2 μM concentration in the Matrigel cell invasion assay.
