|SPOTLIGHTS ON NEW PUBLICATIONS
|Year : 2015 | Volume
| Issue : 1 | Page : 81-83
Spotlights on new publications
Sherif M Abaza MD
Department of Parasitology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
|Date of Submission||27-Apr-2015|
|Date of Acceptance||04-May-2015|
|Date of Web Publication||24-Aug-2015|
Sherif M Abaza
Department of Parasitology, Faculty of Medicine, Suez Canal University, Ismailia
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Abaza SM. Spotlights on new publications. Parasitol United J 2015;8:81-3
| New drug targets|| |
Malaria is the most fatal parasitic disease caused by several species of the genus Plasmodium; however, Plasmodium falciparum has the most significant severity. Chloroquine and pyrimethamine-sulfadoxine have been used as the standard treatment for malaria throughout the last century. This protocol has been substituted by WHO-recommended drugs (artemisinin-based combination therapies) due to the appearance and spread of chloroquine resistance. Recent studies have suggested emerging resistance to the artemisinin family, particularly in Southeast Asia. Schistosomiasis is another parasitic disease with high morbidity and mortality rates. Treatment relies on a sole drug that combines safety and low price (praziquantel). It is active against adult stages, but is limited by its low efficacy against the juvenile stages, thus leading to several reports of high rates of reinfection, treatment failures and emergence of resistant strains. Therefore, a search for new agents working against new targets in these parasites are urgently recommended.
New technology offers several facilities that might help for development of new drug targets. These constitute: 1) A generated large dataset of expressed sequence tags (ESTs) for identification of numerous novel genes; 2) Understanding the molecular architecture of the biology, pathogenesis and host-parasite interactions; 3) Microarray analyses of the parasite's entire transcriptome profile; 4) Integration of the parasite's proteomic, genomic, transcriptomic and immunimic information, and 5) Genetic manipulation of individual genes. Furthermore, development of partially automated three-component screen workflow to interface parasitic stages in vitro with natural and synthetic chemical compounds would speed up identification of novel drug targets.
The present issue will focus on recent publications that dealt with the development of new drug targets against malaria and schistosomiasis.
Malaria: Recent technology permits scientists to approach the development of new drug targets specifically in tropical diseases with reported resistance to existing drugs. Meanwhile, recent data in 'omics' research assisted investigators in exploring and characterizing the functional and biological protein interactions that can be used for novel treatment and control strategy. To standardize topographical data analysis, a large-scale protein-protein interaction network (PPIN) was developed for identification and integration of proteins, as a first step towards understanding possible underlying molecular mechanisms for parasite survival and pathogenesis. In malaria research, Bhattacharyya M. and Chakrabarti S. from India utilized in-silico analysis to identify important interacting proteins (IIPs) in P. falciparum. The PPIN was used to determine the functional interactions relevant for parasite survival, growth, and pathogenesis. Before presenting the compiled research work of the investigators, certain terms require clarification. In a large-scale biological network centrality analysis, the term 'node' is identified as a crucial data for network integrity. Therefore, identification of certain IIPs would lead to recognition of essential nodes for network integrity. In PPIN analysis, it was found that proteins interacting with more than 15 proteins were considered as 'hubs', and hubs in turn were classified as 'party' or 'date' hubs. The first term is given to proteins interacting with other proteins at the same time and location, whereas those that interact at different times and locations were assigned as date hubs. On the other hand, calculated cumulative centrality score (CCS) allowed for ranking of nodes, and proteins with higher CCS and special biological properties were assigned as central proteins (CPs). In addition, the investigators calculated two further scores for these IIPs: global and local network perturbation scores. Both scores measure protein perturbation effects on global and local network environments, respectively.
On performing in-silico analysis with PPIN protocol, the investigators detected 271 proteins as IIPs with crucial roles in P. falciparum network integrity, as well as interaction with several human proteins involved in multiple metabolic pathways. Among them, 177 hub proteins were classified as 52 party and 104 date hubs, while 21 proteins were termed 'ambiguous' for their uncertain connection with other proteins. The majority of the party hubs (65%) were with ribosomal subunit functional involvement, whereas date hubs showed variable functional properties. When functional involvement of each party and date hub was investigated with their specific interactors, all party hubs shared at least 50% of interactors, whereas none of the date hubs had this property. Meanwhile, 132 CPs with significant high CCS were detected among the 271 proteins, and only 80% of them were hubs (53 party, 32 date and 21 ambiguous). Finally, 4 sets of proteins were detected: 1) hubs, 2) CPs, 3) high GNPS, 4) high LNPS; and only 16 proteins belonged to the 4 IIP sets.
The investigators identified seven proteins present in all Plasmodium spp. stages, and three proteins that had no homologs in humans and possess virulent properties, merozoite surface protein, 40S ribosomal subunit and chromodomain helicase protein. The investigators concluded that these 16 proteins that play a major part in Plasmodium spp. homeostatic pathways and survival could be potential drug targets for malaria. They also recommended future similar network analysis on other pathogens to discover their IIPs.
Identification of important interacting proteins in Plasmodium falciparum using large-scale interaction network analysis and in-silico knock-out studies. Malar J; 2015; 14:70.
Schistosomiasis: In an article published by Bruno J. Neves and colleagues from Brazil and Portugal, a systematic strategy was proposed to test potential molecules for development of new drug targets against schistosomiasis. The proposed strategy entails the use of modern drug repositioning by searching for new chemical compounds affecting a specific protein target required for parasite survival (e.g. proteins essential for motility, host penetration, migration, pairing and mating, as well as reproductive, digestive, and excretory processes). The investigators utilized the availability of a comprehensive schistosome genome database and the advanced new computer technology by using in-silico tools for chemogenomic studies. This reduced the cost and time required in the selection of candidates for in vitro and in vivo assays. To achieve their objective, they conducted database screening of 2114 proteins for identification of drugs approved for treatment of human schistosomiasis (i.e. effective against different life stages of S. mansoni). Amino acid sequences of these selected proteins were tested against three databases: therapeutic target database, drug bank database and STITCH. The latter (http://stitch.embl.de/) was developed by German scientists in 2012 to facilitate the study of interactions between proteins and chemicals. It is a database of interactions connecting over 300 000 chemicals and 2.6 million proteins from 1133 organisms. Suspected drug targets were re-evaluated using different techniques to validate their functional regions. For confirmation that their strategy would help scientists to develop new schistosomicidal drugs, they found agreeable results with several drugs previously known to be effective against schistosomiasis, such as clonazepam, auranofin, nifedipine, and artesunate. The systematic strategy allowed the investigators to predict 115 drugs active against 33 drug target proteins, none of which is under experimental research against schistosomiasis and waiting for future studies. Of these 115 predicted drugs, the investigators suggested 61 with potential activity against muscle function on the basis of their interaction with neurotransmitter transporters. Examples of the predictive drug targets that require future studies are: 1) Cinnarizine which is an antagonist of the histamine H1 receptor with inhibitory effect on schistosome as it is a calcium channel blocker. 2) Clotrimazole , an antifungal drug, is another blocker of schistosome Ca 2+ -activated K + channel with inhibition of Ca 2+ and K + movement across the cell membrane. 3) Tetrabenazine , an inhibitor of vesicular monoamine transporter type 2, is able to block the vesicular schistosome amine transporter. 4) Gentamicin , an antibiotic used in treatment of several bacterial infections, was found to interfere with S. mansoni heat shock protein 70 (SmHSP70) involved as chaperone stress protein for development of parasitic life cycle stages and its growth and survival. 5) Griseofulvin , another fungistatic drug, is able to inhibit schistosome tubulin-β chain. 6) Aprindine , an anti-arrhythmic drug, has a high binding affinity to calmodulin which is the primary sensor of intracellular Ca 2+ involved in muscle contraction. Selective calmodulin inhibitors caused in vitro miracidial vesiculation and inhibition of schistosome egg hatching and cercarial penetration processes.
In-silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni. PLoS Negl Trop Dis; 2015; 9(1):e3435.
Schistosomiasis: Imatinib is an anticancer agent with an inhibitory effect on Abelson murine leukemia (Abl). SmAbl1 and SmAbl2 tyrosine kinases (TK) were characterized and detected in schistosome gonads suggesting their role in reproduction. Meanwhile, TKs were extensively evaluated in the last decade for their potential roles in schistosomes development, growth, and survival. Previous studies have demonstrated that both SmTKs were targets for imatinib and had the majority of amino acids that allowed for imatinib binding to human Abl-kinase. In addition, in vitro studies demonstrated imatinib effects on schistosome locomotion, stability, and viability, with significant gastrodermis degradation and schistosome death. Motivated by these data, Svenja Beckmann from Germany worked with a team from USA on the effects of imatinib on adult S. mansoni in experimentally infected rodents. They worked on two S. mansoni isolates obtained from Liberia and Puerto Rico. The experimental infection was conducted using two animal models (mice and hamsters), followed by imatinib treatment with different doses (20-100 mg/kg body weight). However, the results showed no reduction either in worm burden or in egg count. Previous studies reported that imatinib binding to serum albumin (SA) and α-1 acid glycoprotein (AGP) negatively influences their therapeutic activities, and erythromycin competes with imatinib for binding with AGP. Therefore, the investigators examined the effect of SA, AGP and erythromycin on imatinib efficacy on schistosome worms and schistosomula. The collected perfused adult worms (5-10 couples/well) were placed in different culture media (with or without additional SA) and were treated with imatinib for 6 days. They added to the culture media either BSA or human SA to simulate its concentration in vivo. In other culture wells, the investigators added AGP and erythromycin and treated adult worms with imatinib. Thereafter, they evaluated their coupling stability, morphology and survival, as well as egg production. Similar studies were conducted on the schistosomula. Meanwhile, they evaluated the combined actions of SA and AGP on imatinib efficacy. Results showed that without SA addition, schistosome couples died within 6.5 days, whereas couples in media enriched with BSA or human SA displayed decreased movement and vitality after 6.5 days. Similar results were obtained in AGP studies with schistosome death after 4 days, and addition of erythromycin to the culture media containing AGP abolished the inhibitory effect of AGP on imatinib. Combined SA and AGP addition had the strongest negative effects on imatinib efficacy against schistosomes. In contrast, schistosomula when treated with imatinib alone, degeneration and death occurred within 4 days, and when treated in culture medium supplemented with BSA, they were similar to controls. Addition of AGP to the culture also influenced imatinib efficacy. The investigators discussed their results and concluded that both SA and AGP decreased imatinib's efficacy on schistosomulae and worms. They also concluded that rodents are not suitable experimental animals for AGP-sensitive compounds such as imatinib. Instead, they recommended rhesus monkeys and pigs for future studies. In addition, they recommended further studies to solve problematic blockage of AGP and SA on imatinib before experimental animal studies.
Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor imatinib. Int J Parasitol Drugs Drug Resist; 2014; 4(3):287-295.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.