Finding new hits in neglected disease projects: target or phenotypic based screening?

Area of Science:

• Drug discovery and development
• Parasitology
• Medicinal chemistry

Background:

• Neglected tropical diseases (NTDs) like malaria, Chagas disease, leishmaniasis, and human African trypanosomiasis require novel drug discovery strategies.
• Traditional target-based screening faces challenges including target selection issues and rapid resistance development.
• Phenotypic screening offers potential for increased efficacy and slower resistance but can present optimization challenges due to unknown targets.

Purpose of the Study:

• To evaluate the advantages and disadvantages of target-based and phenotypic screening for discovering drugs against NTDs.
• To discuss how technological advancements impact the scalability and effectiveness of both screening strategies.
• To propose an integrated approach for a comprehensive drug discovery portfolio for NTDs.

Main Methods:

• Comparative analysis of target-based screening (high-throughput screening against isolated molecular targets) and phenotypic screening (screening against whole organisms).
• Discussion of technological advancements enabling large-scale, high-quality screening for both approaches.
• Review of challenges and opportunities associated with each screening strategy in the context of NTD drug discovery.

Main Results:

• Target-based screening allows for high-volume identification of potent inhibitors but may lack whole-organism efficacy and is prone to resistance.
• Phenotypic screening increases the likelihood of efficacy and may slow resistance development, though target identification can be complex.
• Recent technological advances have made phenotypic screening scalable, comparable to target-based methods.

Conclusions:

• Neither target-based nor phenotypic screening alone is sufficient for robust NTD drug discovery.
• A comprehensive drug discovery portfolio should integrate both target-based and phenotypic approaches to leverage their respective strengths.
• Combining strategies can mitigate individual weaknesses, leading to more effective and sustainable treatments for neglected tropical diseases.