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New biomolecules to fight drug resistance in Kala- azar (Visceral Leishmaniasis)

About Kala- azar (Visceral Leishmaniasis)

Leishmaniasis is a neglected tropical disease which affects 98 countries including India. It is caused by the protozoan parasite called Leishmania, which is transmitted through the bite of sand flies. The most affected countries of South East Asia Region are Bangladesh, India, Nepal and Bhutan. Also, in India, most affected states are Bihar, Jharkhand, West Bengal and Uttar Pradesh. In fact, India is one amongst the six countries which share 90% of the global burden of leishmaniasis.

There are three main forms of leishmaniasis . These are Visceral, Cutaneous, and Mucocutaneous. Visceral is the most serious form of disease which affects the multiple organs. Cutaneous is the most common form which causes skin sores. Also, Mucocutaneous causes skin and mucosal lesion. In India, Visceral leishmaniasis is commonly known as Kala-azar. It is fatal in over 95% of the cases, if left untreated.

Drugs and Treatment 

Miltefosine is the only oral drug available for the disease. But, it is rapidly losing its effectiveness. This is because of emerging resistance to this drug due to a decrease in its accumulation inside the parasite. This is necessary for the drug to kill the parasite.

Transporter protein is a specific type of protein molecules. It plays a major role in carrying miltefosine into and out of the parasite’s body which comprises of a single cell. A protein, called ‘P4ATPase-CDC50’, is responsible for intake of the drug by the parasite. Also, another protein called ‘P-glycoprotein’, is responsible for throwing this drug out from within the parasite’s body. A decrease in the activity of the former protein, and an increase in the activity of the latter results in less amounts of miltefosine being accumulated inside the parasite’s body. Thus, this causes it to become resistant to the drug.

Recent Research 

A team of researchers at the Department of Biotechnology’s National Centre for Cell Science (DBT-NCCS) in Pune are trying to explore ways to tackle miltefosine resistance. The researchers worked with one of the species of Leishmania that causes infection, called Leishmania major. In fact, they tried to manipulate these transporter proteins in the species in a manner.  It would result in increased uptake of the drug and decrease in its being thrown out of the parasite’s body. In fact, transport proteins exist across a diverse range of organisms from bacteria to mammals, also including humans.

Dr. Singh’s research group used computational methods to design small molecules, called peptides. It could specifically interact with the transporter proteins of L. major alone, and not interfere with human proteins in any way. Also, the peptides were designed to modulate the transporter proteins “allosterically”. Actually, it is done by interacting with the protein molecule at a location other than the specific location where miltefosine binds to it. Thus, this group is the first that have shown allosteric modulation of transporter proteins of Leishmania using computationally-designed synthetic peptides.

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