Past and future of trypanosomatids high-throughput phenotypic screening

Area of Science:

• Parasitology
• Drug Discovery
• Computational Biology

Background:

• Millions are affected by diseases caused by trypanosomatid parasites, primarily in developing nations.
• Current treatments for these diseases are limited by resistance, low efficacy, and high toxicity, necessitating novel drug development.
• The drug discovery process is complex, and while rational drug design aids discovery, it relies on extensive data from methods like high-throughput screening (HTS).

Purpose of the Study:

• To discuss the potential of phenotypic HTS for discovering new drugs against trypanosomatid parasites.
• To highlight the importance of image-based, high-content screening methods in this process.
• To propose an optimized assay cascade for identifying drug candidates for clinical development, using leishmaniasis as a model.

Main Methods:

• Phenotypic high-throughput screening (HTS) is crucial for trypanosomatid drug discovery due to limited validated targets and parasite complexity.
• Image-based, high-content screening methods are emphasized for their role in phenotypic HTS.
• A proposed cascade of assays is outlined for identifying drug candidates for clinical development.

Main Results:

• Phenotypic HTS, particularly image-based approaches, is a vital strategy for identifying bioactive compounds against trypanosomatid parasites.
• The scarcity of validated molecular targets in trypanosomatids makes phenotypic screening an essential tool.
• An ideal assay cascade can streamline the identification of promising drug candidates for leishmaniasis.

Conclusions:

• Phenotypic HTS, especially with high-content imaging, presents a viable strategy for advancing drug discovery for neglected tropical diseases caused by trypanosomatids.
• Developing effective treatments for diseases like leishmaniasis requires innovative screening approaches.
• The proposed assay cascade offers a roadmap for efficient drug candidate selection.