Omics Approaches in Drug Development against Leishmaniasis: Current Scenario and Future Prospects

Abstract

Leishmaniasis is a zoonotic disease transmitted in humans by the bite of Leishmania-infected phlebotomine sandflies. Each year approximately 58,500 cases of leishmaniasis are diagnosed across the globe, with a mortality rate of nearly seven percent. There are over 20 parasitic strains of Leishmania which are known to cause distinct types of leishmaniasis and pose an endemic threat to humans worldwide. Therefore, it is crucial to develop potential medications and vaccines to combat leishmaniasis. However, the task of developing therapeutic solutions is challenging due to Leishmania's digenetic lifecycle. The challenge is further intensified by cases of resistance against the available drugs. Owing to these challenges, the conventional drug development regimen is further limited by target discovery and ligand suitability for the targets. On the other hand, as an added advantage, the emergence of omics-based tools, such as high-end proteomics, transcriptomics and genomics, has hastened the pace of target discovery and target-based drug development. It is now becoming apparent that multi-omics convergence and an inter-connected systems approach is less time-consuming and more cost-effective for any drug-development process. This comprehensive review is an attempt to summarize the current knowledge on the muti-omics approach in drug development against leishmaniasis. In particular, it elaborates the potential target identification from secreted proteins in various stages of Leishmania infection and also illustrates the convergence of transcriptomic and genomic data towards the collective goal of drug discovery. This review also provides an understanding of the potential parasite's drug targets and drug resistance characteristics of the parasite, which can be used in designing effective and specific therapeutics.

Keywords: drug discovery; leishmaniasis; proteomics; structural proteomics; target proteins.

Figure 1

Leishmania is transferred from the bite of the female sandfly. (1) Through blood meals, sandflies infuse the transferable stage, promastigotes. (2) Promastigotes are phagocytized by macrophages when they reach to puncture the wound and are converted into amastigotes. (3) Amastigotes are divided into infected cells and distress numerous tissues. (4) Clinical Leishmania symptoms begin when the sandfly ingests the amastigote. (5) The transmission cycle is completed when an amastigote converts into a promastigote in the sandfly gut.

Figure 2

Omics analysis methods used in the study of Leishmania parasite.

Figure 3

Simplified proteomics workflow of Leishmania proteome: (1) In vitro culture of Leishmania spp. in a medium with promastigote and amastigote forms followed by aliquoting; (2) Centrifugation of the culture and sediment collection; (3) Separation of individual proteins/subunits using 2D-Gel electrophoresis; and (4) deification of individual spots (proteins/subunits) using mass spectrometry.

Figure 4

Secreted protein analysis (1) Leishmania spp. cultured in serum free medium; (2) Centrifuge collected aliquot; (3) Obtained sediment used for the quantification of secreted proteins; (4) Result analyzed by MS.