Unravelling the myth surrounding sterol biosynthesis as plausible target for drug design against leishmaniasis.

The mortality rate of leishmaniasis is increasing at an alarming rate and is currently second to malaria amongst the other neglected tropical diseases. Unfortunately, many governments and key stakeholders are not investing enough in the development of new therapeutic interventions. The available treatment options targeting different pathways of the parasite have seen inefficiencies, drug resistance, and toxic side effects coupled with longer treatment durations. Numerous studies to understand the biochemistry of leishmaniasis and its pathogenesis have identified druggable targets including ornithine decarboxylase, trypanothione reductase, and pteridine reductase, which are relevant for the survival and growth of the parasites. Another plausible target is the sterol biosynthetic pathway; however, this has not been fully investigated. Sterol biosynthesis is essential for the survival of the Leishmania species because its inhibition could lead to the death of the parasites. This review seeks to evaluate how critical the enzymes involved in sterol biosynthetic pathway are to the survival of the leishmania parasite. The review also highlights both synthetic and natural product compounds with their IC50 values against selected enzymes. Finally, recent advancements in drug design strategies targeting the sterol biosynthesis pathway of Leishmania are discussed.

The Search for Putative Hits in Combating Leishmaniasis: The Contributions of Natural Products Over the Last Decade.

Despite advancements in the areas of omics and chemoinformatics, potent novel biotherapeutic molecules with new modes of actions are needed for leishmaniasis. The socioeconomic burden of leishmaniasis remains alarming in endemic regions. Currently, reports from existing endemic areas such as Nepal, Iran, Brazil, India, Sudan and Afghanistan, as well as newly affected countries such as Peru, Bolivia and Somalia indicate concerns of chemoresistance to the classical antimonial treatment. As a result, effective antileishmanial agents which are safe and affordable are urgently needed. Natural products from both flora and fauna have contributed immensely to chemotherapeutics and serve as vital sources of new chemical agents. This review focuses on a systematic cross-sectional view of all characterized anti-leishmanial compounds from natural sources over the last decade. Furthermore, IC50/EC50, cytotoxicity and suggested mechanisms of action of some of these natural products are provided. The natural product classification includes alkaloids, terpenes, terpenoids, and phenolics. The plethora of reported mechanisms involve calcium channel inhibition, immunomodulation and apoptosis. Making available enriched data pertaining to bioactivity and mechanisms of natural products complement current efforts geared towards unraveling potent leishmanicides of therapeutic relevance.