|LETTER TO EDITOR
|Year : 2017 | Volume
| Issue : 1 | Page : 49-50
Utility of aptamers for antileishmanial drug targets: A potential hypothesis
Masoud Keighobadi1, Abbas Khonakdar Tarsi2, Mahdi Fakhar3, Saeed Emami4
1 Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
2 Department of Biochemistry, Biophysic, and Gentic, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
3 Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
4 Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
|Date of Acceptance||15-Feb-2017|
|Date of Web Publication||16-Mar-2017|
Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari
|How to cite this article:|
Keighobadi M, Tarsi AK, Fakhar M, Emami S. Utility of aptamers for antileishmanial drug targets: A potential hypothesis. Trop Parasitol 2017;7:49-50
Leishmaniasis is a group of tropical diseases with a significant clinical and epidemiological diversity and is caused by protozoan parasite genus Leishmania and is widespread in many parts of the world, especially in Asia, Africa, and Latin America. It is estimated that about 350 million people are at risk of infection worldwide; leishmaniasis has a serious impact on global public health. Currently, there is no effective vaccine for leishmaniasis. Therefore, the treatment of leishmaniasis relies primarily on chemotherapy. The available drugs have various shortcomings such as parenteral administration, long-term of treatment, drug resistance, toxic side effects, and high cost of treatment.
Antileishmanial drug discovery has been fuelled in recent years by a variety of factors including whole-genome sequencing and drug target pathway. Some of the metabolic pathways are essential as potential drug targets in Leishmania such as glycolytic pathway, sterol biosynthetic pathway, and trypanothione pathway. Glycolytic pathway is important in Leishmania life cycle and is a membrane-enclosed organelle that contains the glycolytic enzymes. Furthermore, the energy metabolism of Leishmania exclusively depends on the carbon sources available in the host. Since there is no Krebs cycle in Leishmania, they use glycolysis as the solely source of adenosine triphosphate generation. This pathway is used to break down long chain fatty acids for their carbon and energy in Leishmania. Since given that glycolysis is the only source of energy for these parasites, it could serve as a promising drug target and glycosome assembly requires the special type of proteins called peroxins (PEX). Both PEX5 and PEX7 are the cytosolic receptors for other glycosomal proteins which bind and move them into the organelles. Thus, inhibition of the synthesis of PEX5 and PEX7 can be considered as a novel potential therapeutic target.
Therefore, the high burden of leishmaniasis in some parts of the world, its severe harmful clinical effects, and the lack of an appropriate medication with the least side effects on the host is of the great stimulations to study the molecular basis of metabolic processes and pathogenicity of the parasite. These investigations in addition to show the mechanisms of pathogenesis and complications arising from them can also be useful in determining appropriate drug targets. The process of gene expression or transcription and protein synthesis route with the guidance of stored information in DNA of all living organisms is of particular importance. Indeed, DNA exerts controls on actions of organism such as metabolism, growth, and reproduction through regulation of protein synthesis. Thus, the different steps of gene expression can be a good place for drug intervention.
As noted above, glycosomes are the vital organelles for the survival of the parasite in which occur many essential reactions. The organelles are created from the joining buds of the endoplasmic reticulum. The interesting thing is that to assembly of an active glycosome, various proteins are synthesized in the cytosol of the parasite and then transferred to the organelles. The protein translocation in parasite needs two other important proteins named PEX5 and PEX7. These PEX are receptor proteins which bind to glycosomal proteins and transfer them to the membrane or matrix of these organelles. Hence, if synthesis of PEX is inhibited in the process of assembly or propagation of glycosome, the parasite development and proliferation will be stopped due to lack of accessibility to glycosomal proteins.
The current methods of inhibiting protein synthesis in eukaryotes produce severe side effects in humans. Hence, to obtain the desired result, inhibitors must specifically suppress the process in parasites. Aptamers are small polynucleotides (25–100 nucleotides) which can be synthesized. One of the new methods that can be used to control of target genes expression is employing of specific single-stranded DNA or RNA antibodies named by chemical or enzymatic methods or a combination of the two; these can identify specific molecular targets by forming a secondary or tertiary.
Given the importance of PEX (PEX 5 and 7) in survival and proliferation of Leishmania, first, specific aptamer can be designed against to the PEX' messenger RNA (mRNA). In the next step, an antibiotic such as puromycin (inhibitor of protein synthesis) can be conjugated to the aptamer by chemical methods. The aptamer attached antibiotic can bind to its specific mRNA and able to inhibit its translation. However, because other types of mRNA including hosts' mRNAs are not recognized and bound by the aptamer, the protein synthesis in host remains intact and unaffected by the antibiotic. Thus, by this method, PEX' gene expression can be inhibited in the translation step which jeopardizes the lives of parasite and saves the person who is falling. Experimental studies on this topic in murine model are warranted. We suggest that this subject could be evaluated in steps of in vitro and in vivo or ex vivo experiments.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sharma U, Singh S. Insect vectors of Leishmania
: Distribution, physiology and their control. J Vector Borne Dis 2008;45:255-72.
Andrews KT, Fisher G, Skinner-Adams TS. Drug repurposing and human parasitic protozoan diseases. Int J Parasitol Drugs Drug Resist 2014;4:95-111.
Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, et al.
Visceral leishmaniasis: Current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2002;2:494-501.
Peacock CS, Seeger K, Harris D, Murphy L, Ruiz JC, Quail MA, et al.
Comparative genomic analysis of three Leishmania
species that cause diverse human disease. Nat Genet 2007;39:839-47.
Opperdoes FR. Compartmentation of carbohydrate metabolism in trypanosomes. Annu Rev Microbiol 1987;41:127-51.
Parsons M. Glycosomes: Parasites and the divergence of peroxisomal purpose. Mol Microbiol 2004;53:717-24.
Parsons M, Furuya T, Pal S, Kessler P. Biogenesis and function of peroxisomes and glycosomes. Mol Biochem Parasitol 2001;115:19-28.
Mayer G. The chemical biology of aptamers. Angew Chem Int Ed Engl 2009;48:2672-89.