Abstract
Cutaneous leishmaniasis is the most common form of leishmaniasis, caused by Leishmania major and is spread by the bite of a sandfly .This species infects the macrophages and dendritic cells Due to multi-drug resistance, there is a need for a new therapeutic technique. Recently, a novel molecular motor of Leishmania, Myosin XXI, was classified and characterized. In addition, the drug resistance in this organism has been linked with the overexpression of ABC transporters. Systems biology aims to study the simulation and modeling of natural biological systems whereas synthetic biology deals with building novel and artificial biological parts and devices Together they have contributed enormously to drug discovery, vaccine design and development, infectious disease detection and diagnostics. Synthetic genetic regulatory networks with desired properties, like toggling and oscillation have been proposed to be useful for gene therapy. In this work, a nanocircuit with coupled bistable switch - repressilator has been designed, simulated in the presence and absence of inducer, in silico, using Tinker Cell. When inducer is added, the circuit has been shown to produce reporter at high levels, which will impair the activity of Myosin XXI and ABC transporters. Validation of the circuit was also performed using GRENITS and BoolNet. The influence of inducer on the working of the circuit, i.e., the type of gene expression, response time delay, the steady states formed by the circuit and the quasipotential landscape of the circuit were performed. It was found that the addition of inducer reduced the response time delay in the graded type of gene expression and removed the multiple intermediate attractors of the circuit. Thus, the inducer increased the probability of the circuit to be present in the dominant stable state with high reporter concentration and hence the designed nanocircuit may be used for the treatment of leishmaniasis .
Highlights
Leishmaniasis is a neglected tropical disease, caused by the protozoan parasite of the genus Leishmania
As an approach to devise a novel therapeutic strategy and to fight leishmanial drug resistance, this study aims to target the molecular motor, Myosin XXI, as well as ABC transporters of L. major
The basic idea of this study is that impairments of the targets can be brought about by either antisense RNA for the most potential calmodulin binding motif of Myosin XXI or Phosphatase 2A (PP2A), which dephosphorylates Myosin XXI and ABC transporters
Summary
Leishmaniasis is a neglected tropical disease, caused by the protozoan parasite of the genus Leishmania. It mainly infects macrophages and dendritic cells of the immune system. Studies on Myosin XXI have shown that it is very important for the survival of the parasite and that it is the only myosin isoform present in the organism (Batters et al, 2014). It is present only in the Leishmania genus, with less than 35% identity with other myosin isoforms. The intracellular trafficking activity of Myosin XXI will be affected to a great extent, leading to the death of the parasite
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