How many tropical diseases do you know of? Malaria, dengue and sleeping sickness immediately come to mind. Maybe leprosy, if you think hard enough. But, many of us may not have heard of cutaneous leishmaniasis, a less dangerous but much more prevalent cousin of kala azar or black fever. Cutaneous Leishmaniasis (CL) is caused by the protozoan Leishmania parasites which are transmitted by the bite of infected female sandflies. A team of researchers led by Dr. Shailza Singh from the National Centre for Cell Science (NCCS), Pune have been studying this disease extensively and have now discovered a new lead compound to help combat this neglected tropical disease. Dr. Sudipta Basu and his team from Indian Institute of Science Education and Research (IISER), Pune have co-authored this work.
Often called white leprosy, CL is known to cause skin lesions and ulcers on exposed parts of the body, while often leaving behind life-long scars and severe disabilities. According to statistics by WHO, around 0.9 – 1.3 million new cases of leishmaniasis surface every year, leading to up to 20,000 to 30,000 deaths annually. High-risk factors identified for being susceptible to this disease include poverty, malnutrition, population displacement, poor housing, and a weak immune system. Leishmaniasis thus, pre-dominantly affects the populations of lesser developed countries. A lack of sufficient medical funding and research to find potential cures for leishmaniasis in these countries only aggravates the problem further.
Conventional methods of treating CL include administration of antimony based compounds or oral, topical or liposomal preparations of anti-fungal compounds. However, these approaches have increasingly been proving ineffective, insufficient or too expensive to use, while the problem of drug resistance further aggravates the situation. Thus, it has become paramount to identify new compounds that could be used to treat leishmaniasis.
Several natural compounds such as alkaloids, phenolic compounds, terpenes and saponins have anti-leishmanial properties. But, recent studies have found a class of anti-fungal compounds called ‘coumarins’ that also possess anti-protozoan properties. In order to take this lead forward, researchers from NCCS, Pune comprehensively surveyed several coumarin derivatives for their therapeutic efficacy against leishmaniasis, and in this pursuit also collaborated with the team at IISER Pune. However, the mechanistic aspects of the drug’s function stillremains to be elucidated further.
“Our goal was to explore the possibility of using coumarin derivatives as anti-leishmanial agents. Towards this we have designed a set of coumarin derivatives using computer aided drug designing, which could serve asprobable drug candidates for the treatment of leishmaniasis,” explains Dr. Shailza Singh of NCCS, who is also the corresponding author of this study.
Their initial screening led to the identification of some 1000 odd compounds, which were ultimately narrowed down to 5 promising drug candidates, based on various judging criteria like 3D shape, size, and chemical functionality. After the physical and chemical properties based selection, the scientists wanted to test these 5 drug candidates for their biological activity and compatibility. They performed various microbiological experiments in this regard, and arrived at one of the compounds which showed the best anti-leishmanial properties, nicknamed ‘C2’ (compound 2). C2 was shown to cause a reduction in size and mobility of the parasitic protozoan cells, and also attenuated their ability to infect macrophages, the specialized infection-fighting cells of higher animals.
Further, the scientists took experimental mice infected with cutaneous leishmaniasis lesions, and then treated them with oral doses of C2. To their surprise, the leishmanial lesions in mice reduced in size by almost 50%. “It was particularly interesting to observe the effect of the compound in mice, since we did not anticipate such a drastic effect at all,” remarks Dr. Singh.
C2 can thus serve as a basal drug candidate which, with further modification and development, can be used as a potent anti-leishmanial compound. Dr. Singh feels that the present study is an important step towards identifying new drug candidates like coumarins with largely underexplored therapeutic potential, especially given the limited number of oral anti-leishmaniasis drugs available currently.
“Research on neglected tropical diseases needs to be strengthened especially in countries like India where cases of drug resistance are common and therefore there is always a need for newer medications,” she signs off.