Figure 1 - uploaded by Ian Fairweather
Content may be subject to copyright.
Highly schematic diagram of the organisation of microtubule-containing structures in a typical unicellular eukaryote. A. Cross-section through a fl agellum showing the 9 + 2 arrangement of microtubules. The nine peripheral doublet microtubules are termed A-and B-tubules and attached to the A-tubule are the inner and outer dynein arms that project to the next adjacent doublet (not shown) and the radial spokes that project to the central pair. B. Cytosolic microtubular cytoskeleton acting as a track for the kinesin-mediated transport of an intracellular vesicle. C. Spindle microtubules extending from microtubule-organising centres (MTOC) to kinetochores (the points of attachment to chromosomes) during the metaphase stage of cell division. In addition, note the submembrane microtubules, which are important for cell shape in many cells (in diagram of cell).
Source publication
Background:
Parasitic diseases including malaria, leishmaniasis and schistosomiasis take a terrible toll of human life, health and productivity, especially in tropical and subtropical regions, and are also highly significant in animal health worldwide. Antiparasitic drugs are the mainstays of control of most of these diseases, but in many cases cu...
Contexts in source publication
Context 1
... have important functions in cell division (as the principal components of the mitotic spindle), maintenance of shape and polarity (as components of the cytoskeleton), motility (as the principal components of cilia and flagella), intracellular transport and signal transduction (see Figure 1 and [7] for a review). Their ability to assemble and disassemble reversibly lies at the heart of their func- tional roles in the cell, as for example in mitosis, which requires complex temporal changes in spindle architecture. ...
Context 2
... take on highly diverse arrangements in protozoal parasites but are believed to perform the same kinds of functions as in other eukaryotic cells and are equally essential to cell growth and proliferation ( Figure 1 ). The arrangements of the microtubular cytoskeletons are vastly different between different protozoa: other reviews can be consulted for details [10][11][12] . ...
Similar publications
Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate pharmacological effects of drugs in target organs or cells in vivo. This underscores the increasing need to improve the types and qualities of cellular pharmacokinetic information for drug pr...
The generally accepted view is that the 3,4,5-trimethoxy-substituted aromatic A-ring of combretastatin A-4 (CA-4) and its analogues should be conserved in order to maintain biological activity through enforcing an active molecular conformation. Contrary to this, we have found that substituting the larger meta-methoxygroups of CA-4 with smaller halo...
Appropriate function of the neocortex depends on timely generation and migration of cells produced in the germinal zones of
the neocortex and ganglionic eminence (GE). Failure to accurately complete migration results in cortical dysplasia, a developmental
syndrome implicated in many neurologic disorders. We developed a model of cortical dysplasia i...
Zinc sulphide is one of the commercially important II-VI semiconductors having a wide band gap, rendering it a very attractive material for optical application especially in nanocrystalline form. Nanocomposites of ZnS and ZrS2/ZnS were prepared by simple electrochemical method; their photocatalytic properties had been investigated. The structure, c...
The objective of this work was to characterize the in vitro development of 'Ouro' banana after polyploidization with antimitotics. Shoot apexes were subjected to the following treatments for 24 and 48 hours: amiprophos-methyl (APM), at 0, 10, 20, 30, 40, and 60 μmol L-1; caffeine, at 3, 6, 9, and 12 g L-1; and colchicine, at 2.5 mmol L-1. Survival,...
Citations
... List of orthologues described as drug and vaccine target candidates from different hematophagous parasites including Trematoda, Nematoda and Apicomplexa found in the EVs' proteomic study using Sparicotyle chrysophrii, Protopolystoma xenopodis, Gyrodactylus salaris and Microcotyle sebastis proteomes as reference maker-contig_12610_pilon_pilon-snap-gene−0.5-mRNA-1Tubulin[110] maker-contig_8332_pilon_pilon-augustus-gene−0.19-mRNA-1 ...
Background
Helminth extracellular vesicles (EVs) are known to have a three-way communication function among parasitic helminths, their host and the host-associated microbiota. They are considered biological containers that may carry virulence factors, being therefore appealing as therapeutic and prophylactic target candidates. This study aims to describe and characterise EVs secreted by Sparicotyle chrysophrii (Polyopisthocotyla: Microcotylidae), a blood-feeding gill parasite of gilthead seabream (Sparus aurata), causing significant economic losses in Mediterranean aquaculture.
Methods
To identify proteins involved in extracellular vesicle biogenesis, genomic datasets from S. chrysophrii were mined in silico using known protein sequences from Clonorchis spp., Echinococcus spp., Fasciola spp., Fasciolopsis spp., Opisthorchis spp., Paragonimus spp. and Schistosoma spp. The location and ultrastructure of EVs were visualised by transmission electron microscopy after fixing adult S. chrysophrii specimens by high-pressure freezing and freeze substitution. EVs were isolated and purified from adult S. chrysophrii (n = 200) using a newly developed ultracentrifugation-size-exclusion chromatography protocol for Polyopisthocotyla, and EVs were characterised via nanoparticle tracking analysis and tandem mass spectrometry.
Results
Fifty-nine proteins involved in EV biogenesis were identified in S. chrysophrii, and EVs compatible with ectosomes were observed in the syncytial layer of the haptoral region lining the clamps. The isolated and purified nanoparticles had a mean size of 251.8 nm and yielded 1.71 × 10⁸ particles · mL⁻¹. The protein composition analysis identified proteins related to peptide hydrolases, GTPases, EF-hand domain proteins, aerobic energy metabolism, anticoagulant/lipid-binding, haem detoxification, iron transport, EV biogenesis-related, vesicle-trafficking and other cytoskeletal-related proteins. Several identified proteins, such as leucyl and alanyl aminopeptidases, calpain, ferritin, dynein light chain, 14–3–3, heat shock protein 70, annexin, tubulin, glutathione S-transferase, superoxide dismutase, enolase and fructose-bisphosphate aldolase, have already been proposed as target candidates for therapeutic or prophylactic purposes.
Conclusions
We have unambiguously demonstrated for the first time to our knowledge the secretion of EVs by an ectoparasitic flatworm, inferring their biogenesis machinery at a genomic and transcriptomic level, and by identifying their location and protein composition. The identification of multiple therapeutic targets among EVs' protein repertoire provides opportunities for target-based drug discovery and vaccine development for the first time in Polyopisthocotyla (sensu Monogenea), and in a fish-ectoparasite model.
Graphical Abstract
... Human tubulins and S. mansoni's αand β-tubulin share ∼ 96% and ∼ 91% similarities in sequences, respectively. It is possible that compounds that bind to mammalian tubulin might affect the parasite's ability to carry out MT-mediated activities [49][50][51]. Some authors recently conducted a series of invitro whole-organism screens (of a target-based compound library) against S. mansoni adults and somules to examine the potential of various classes of tubulinbinding molecules as antischistosomal leads. ...
... Some authors recently conducted a series of invitro whole-organism screens (of a target-based compound library) against S. mansoni adults and somules to examine the potential of various classes of tubulinbinding molecules as antischistosomal leads. They identified numerous biologically active compounds, among which phenylpyrimidines were the most promising agents [49][50][51]. ...
Neglected tropical diseases (NTDs) are prevalent in tropical and subtropical countries, and schistosomiasis is among the most relevant diseases worldwide. In addition, one of the two biggest problems in developing drugs against this disease is related to drug resistance, which promotes the demand to develop new drug candidates for this purpose. Thus, one of the drug targets most explored, Schistosoma mansoni Cathepsin B1 (SmCB1 or Sm31), provides new opportunities in drug development due to its essential functions for the parasite's survival. In this way, here, the latest developments in drug design studies targeting SmCB1 were approached, focusing on the most promising analogs of nitrile, vinyl sulphones, and peptidomimetics. Thus, it was shown that despite being a disease known since ancient times, it remains prevalent throughout the world, with high mortality rates. The therapeutic arsenal of antischistosomal drugs consists only of praziquantel, which is widely used for this purpose and has several advantages, such as efficacy and safety. However, it has limitations, such as the impossibility of acting on the immature worm and exploring new targets to overcome these limitations. SmCB1 shows its potential as a cysteine protease with a catalytic triad consisting of Cys100, His270, and Asn290. Thus, design studies of new inhibitors focus on their catalytic mechanism for designing new analogs. In fact, nitrile and sulfonamide analogs show the most significant potential in drug development, showing that these chemical groups can be better exploited in drug discovery against schistosomiasis. We hope this manuscript guides the authors in searching for promising new antischistosomal drugs.
... Continued polymerization of microtubules. [53,54] Macrocyclic Lactones Modulating the glutamate-gated chloride channel. ...
Helminth parasitic infections are a considerable constraint to the livestock industries worldwide. Nematode parasites cause the major proportion of harm to livestock. The infections caused are accountable for severe economic losses in cattle, goat and sheep farming industries. Morbidity and mortality in livestock due to parasitic diseases are increasing alarmingly. Also, their zoonotic influence on human health is considered significant. Anthelmintic drugs have been developed occasionally to curb this disease and prevent major losses. But the development of resistance against these drugs has put another constraint on this flourishing industry. Helminth parasites have developed resistance against three main classes of anthelmintics: benzimidazoles, macrocyclic lactones and nicotinic agonists. With the intensification of resistance, various screening and confirmatory tests have been developed for the speedy introduction of newer drugs in the livestock industry. At the same time, designing and launching novel anthelmintics is time-consuming and economically restrained. Phytochemicals attract much attention because of their pharmacotherapeutic potential, least toxic profile and low environmental hazards. A lot of work is going on plant-based anthelmintic drugs throughout the world. Plants possessing anthelmintic activity have been found efficacious against gastrointestinal parasites. Nevertheless, these herbal medicines have various drawbacks, which include poor efficacy and the absence of target selectivity. These problems are now being taken care of with the help of nanotechnology. Nanoparticles improve the drug's effectiveness, enhance drug delivery, and target selectivity at specific sites. A comprehensive literature survey was carried out via electronic searches of Google Scholar, PubMed, MEDLINE, Science Direct, Scopus and Cochrane Library databases and based on inclusion and exclusion criteria; articles were selected for this review. The review aims at providing a comprehensive overview of plant-based nanoparticles as therapeutic alternatives over conventional synthetic anthelmintic drugs. It also encompasses the methods of detection of resistance and the ways to overcome this menace. The effectiveness of various organic and inorganic nanoparticles against helminthes is also discussed in this review.
... Albendazole binds to beta-tubulin in the helminth and prevents its polymerization, thereby hindering glucose absorption in the parasite 14,15 . Moreover, its inhibitory effect on tubulin polymerization leads to a reduction in cytoplastic microtubules 16 . Albendazole is commonly used before and after surgery as a routine treatment for hydatid cysts 17,18 . ...
Introduction: Hydatidosis, caused by the larval stage of Echinococcus granulosus, is a prevalent parasitic disease affecting both humans and animals. Albendazole is currently the most effective drug for treating hydatid cysts. This research aimed to investigate the histopathological and biochemical effects of Albendazole on the liver, lung, and kidney of mice experimentally infected by hydatid cysts. Materials and methods: A total of 20 mice weighing approximately 220 g were used. The rats were randomly divided into the Albendazole group (100 mg/kg/day) and the control group (infected Rats without treatment). At the end of the experiment, tissue samples from the liver, lung, and kidney were collected for histopathological evaluation. Liver blood tests were used to assess liver functions or liver injury (alkaline phosphatase, alanine aminotransferase, and bilirubin). Results: After 30 days of daily treatment, the total numbers of cysts, size, and weight of the largest cyst were significantly lower in the Albendazole group, compared to the control group. The study addressed histopathological changes in the liver, kidneys, and lungs caused by hydatid cysts, such as tissue necrosis, hemorrhage, and local inflammation, indicating the potential for serious complications and significant damage to these organs. The group treated with Albendazole showed severe histopathological changes in the liver, kidneys, and lungs, compared to the control group. This suggests that Albendazole may trigger a more aggressive response in these organs to the cysts, leading to increased tissue damage. In addition, alkaline phosphatase, alanine aminotransferase, and bilirubin concentrations revealed a significant increase in the Albendazole group. Conclusion: While Albendazole is an effective drug for treating hydatidosis, it can also cause severe side effects on various organs in the body. Therefore, alternative treatment strategies need to be developed to minimize these adverse effects.
... Cytoskeletal microtubules are involved in a variety of cellular processes, including cellular structure and the separation of chromosomes during mitosis [89]. They are also the targets of the benzimidazole class of anthelmintics [90]. In eukaryotes, the genes encoding these microtubule proteins, αand β-tubulin, generally form a large family, with distinct transcription encompassing cohorts of genes displaying constitutive expression as well as genes with cell-specific transcription [91]. ...
In the past decade significant advances in our understanding of liver fluke biology have been made through in-depth interrogation and analysis of evolving Fasciola hepatica and Fasciola gigantica omics datasets. This information is crucial for developing novel control strategies, particularly vaccines necessitated by the global spread of anthelmintic resistance. Distilling them down to a manageable number of testable vaccines requires combined rational, empirical, and collaborative approaches. Despite a lack of clear outstanding vaccine candidate(s), we must continue to identify salient parasite-host interacting molecules, likely in the secretory products, tegument, or extracellular vesicles, and perform robust trials especially in livestock, using present and emerging vaccinology technologies to discover that elusive liver fluke vaccine. Omics tools are bringing this prospect ever closer.
... For example, plant tubulin and Apicomplexan tubulins have a much lower affinity for colchicine than animal tubulin (Morejohn and Fosket, 1991). In contrast, small synthetic molecules such as dinitroanilines bind specifically plant and Apicomplexa tubulins but not vertebrate or fungi ones (Morejohn et al., 1987;Hugdahl and Morejohn, 1993;Fennell et al., 2008;Lyons-Abbott et al., 2010). These observations imply that some structural differences do exist in the architecture of drug-binding sites on tubulin from plants and Apicomplexa on the one hand and mammalian tubulin on the other hand. ...
Compounds targeting microtubules are widely used in cancer therapy with a proven efficacy. However, because they also target non-cancerous cells, their administration leads to numerous adverse effects. With the advancement of knowledge on the structure of tubulin, the regulation of microtubule dynamics and their deregulation in pathological processes, new therapeutic strategies are emerging, both for the treatment of cancer and for other diseases, such as neuronal or even heart diseases and parasite infections. In addition, a better understanding of the mechanism of action of well-known drugs such as colchicine or certain kinase inhibitors contributes to the development of these new therapeutic approaches. Nowadays, chemists and biologists are working jointly to select drugs which target the microtubule cytoskeleton and have improved properties. On the basis of a few examples this review attempts to depict the panorama of these recent advances.
... This is due to the presence of mutations at different positions on the tubulin sequences of different species [3]. Tubulin represents an excellent target in many helminths for anti-tubulin therapies [4]. In nematodes, they are selectively targeted by benzimidazole anthelmintics including albendazole and fenbendazole, by inhibiting or destabilizing microtubule polymerization. ...
... However, the main drawbacks of various compounds that act as tubulin targeting agents are drug resistance and toxicity [3,4,8,9]. For example, clinical trials of some tubulin stabilizers, such as taxanes and vinca alkaloids, have been discontinued due to toxicity and drug resistance [8,9]. ...
Microtubules are receiving enormous interest in drug discovery due to the important roles they play in cellular functions. Targeting tubulin polymerization presents an excellent opportunity for the development of anti-tubulin drugs. Drug resistance and high toxicity of currently used tubulin-binding agents have necessitated the pursuit of novel drug candidates with increased therapeutic potency. The design of novel drug candidates can be achieved using efficient computational techniques to support existing efforts. Proteochemometric (PCM) modeling is a computational technique that can be employed to elucidate the bioactivity relations between related targets and multiple ligands. We have developed a PCM-based Support Vector Machine (SVM) approach for predicting the bioactivity between tubulin receptors and small, drug-like molecules. The bioactivity datasets used for training the SVM algorithm were obtained from the Binding DB database. The SVM-based PCM model yielded a good overall predictive performance with an area under the curve (AUC) of 87%, Matthews correlation coefficient (MCC) of 72%, overall accuracy of 93%, and a classification error of 7%. The algorithm allows the prediction of the likelihood of new interactions based on confidence scores between the query datasets, comprising ligands in SMILES format and protein sequences of tubulin targets. The algorithm has been implemented as a web server known as TubPred, accessible via http://35.167.90.225:5000/.
... This is in line with a report published by Hailegebriel et al. [27] wherein His meta-analysis revealed that praziquantel has an 89.8% cure rate for treating human schistosomiasis in Ethiopia after a single dosage. The existence of secondary metabolites that rendered the medications more available at their site of action, thereby potentiating anthelmintic drugs, might be attributable to the elevated activities of albendazole and mebendazole in the presence of sub-anthelmintic concentrations of BME (0.125 and 0.25 mg/mL) [28]. Praziquantel alone produced characteristic paralytic activity and in the presence of BME, its activity was enhanced against the L. terrestris compared to albendazole and mebendazole indicating a resistance modulation activity of the extract. ...
Helminths in recent times are said to be highly resistant to anthelmintic therapeutics. The level of attention paid to this area is quite low, therefore causing a serious threat to humans and livestock. Helminth’s infection is rampant in developing countries contributing significantly to economic losses and food security in general. This study aims to determine the Anthelmintic properties of methanol extract of Bridelia micrantha (Hochst) Baill leaves. Methods: The anthelmintic activity of helminths was determined by exposure to various concentrations of reference anthelminthic (albendazole, praziquantel and mebendazole) drugs and plant extract. Measurements were taken based on times for death and paralysis. Results: The extract exhibited a concentration-dependent anthelmintic activity against Lumbricus terrestris with significant (p < 0.0001) paralysis and death times when the extract concentrations were 4, 8, 16 and 32 mg/mL respectively. In the presence of 0.125 mg/mL of the extract the reference anthelmintic (albendazole), showed a potentiated activity against the test organism. In the presence of 0.25 mg/mL of the extract the reference anthelmintic (mebendazole), also showed a potentiated activity against the test organism. In the presence of 0.125 and 0.25 mg/ml of the extract, the reference anthelmintic (praziquantel) showed similar results. Conclusion: The extract had anthelmintic activity against L. terrestris and modified the resistance of the organism to albendazole, mebendazole and praziquantel.
... When subminimal inhibitory concentration of the extracts was combined with albendazole, it was found that only PPSe greatly potentiated the anthelminthic effect of albendazole. e enhanced activity of albendazole could be due to presence of secondary metabolites in the PPSe that rendered the drugs more available at their sites of action thus potentiating the anthelmintic effect [25,27,30]. e combination of CPSe, PPLe, and CPLe inhibited the parasitic effect of albendazole on the earthworms. ...
The most common diseases that affect low-income countries are helminthosis and trypanosomosis. In Ghana, and in many other African countries, herbal treatment of various diseases is still common. In the present study, we sought to determine the antitrypanosomal and anthelminthic activities of Carica papaya and Ceiba pentandra. The ethanol extracts of Carica papaya stem bark (PPSe) and leaves (PPLe) and ethanol extracts of Ceiba pentandra stem bark (CPSe) and leaves (CPLe) were screened against Trypanosoma brucei brucei and Pheretima posthuma worms in vitro. CPSe exhibited strong antitrypanosomal activity, while the other extracts exhibited moderate activity against T. b. brucei. All the extracts showed weak selective indices (SI) when tested on Jurkat cell lines, which is indicative of a potential toxic effect. When the extracts were screened against P. posthuma worms, only PPSe and CPSe were able to kill the worms after the exposure time at concentrations of 2.5, 5, and 10 mg/mL. PPSe was again the only extract that potentiated the anthelminthic activity of albendazole against P. posthuma worms. Preliminary phytochemical screening and GC-MS analysis revealed the presence of compounds with antitrypanosomal and anthelminthic properties. The results confirmed the potential of C. papaya and C. pentandra as remedies for trypanosomosis and helminthosis and also gives credence to their folkloric use.
... For colchicine on the α-tubulin subunit, benzimidazole derivatives can alter the function and structure of microtubules in parasite cells [24], promoting depolymerization and assemble inhibition of microtubules [25,26]. Thus, vital activities inside the parasite cell are altered or inhibited, such as the movement of organelles, transport of secretion vesicles, cellular displacement, movement of chromosomes during the cellular division or absorptions of some nutrients [27,28]. ...
... Substituents optimization on benzimidazole allowed the development of compounds with improved efficiency, such as albendazole 2 and mebendazole 3 ( Fig. 1) [16,28]. The additional substituents in C-5 or C-6 improved their pharmacokinetics and antiparasitic activity spectrum, putting them in a key position to modulate drug activity impact. ...
... It has also been demonstrated that benzimidazole compounds inhibited the formation of human cancer cell lines [27,28]. Some examples with antitumor activity [13] are bendamustine 31, binimetinib, veliparib 32, abemaciclib and pracinostat 33 (Fig. 4) [58,59]. ...
The therapeutic potential of the benzimidazole nucleus dates back to 1944, being and important heterocycle system due to its presence in a wide range of bioactive compounds such as antiviral, anticancer, antibacterial, and so on, where optimization of substituents in this class of pharmacophore has resulted in many drugs. Its extensive biological activity is due to its physicochemical properties like hydrogen bond donor-acceptor capability, stacking interactions, coordination bonds with metals as ligands and hydrophobic interactions; properties that allow them to easily bind with a series of biomolecules, including enzymes and nucleic acids, causing a growing interest in these types of molecules. This review aims to present an overview to leading benzimidazole derivatives, as well as to show the importance of the nature and type of substituents at the N1, C2, and C5(6) positions, when they are biologically evaluated, which can lead to obtaining potent drug candidate with significant range of biological activities.
