Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Area of Science:

• Malariology and Parasitology
• Medicinal Chemistry
• Drug Discovery

Background:

• Targeting Plasmodium parasites requires chemical matter effective against diverse life cycle stages.
• Existing antimalarials often lack efficacy across all parasite developmental phases.

Purpose of the Study:

• To conduct a de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against multiple Plasmodium parasite life cycle stages.
• To identify novel chemotypes with either multi-stage or stage-specific antimalarial activity, including transmission-blocking potential.

Main Methods:

• Parallel screening of the MMV Pandemic Response Box against Plasmodium asexual, liver-stage parasites, gametocytes (IV/V), gametes, and oocysts.
• Evaluation of compounds as endectocides.
• Mechanistic studies on identified active compounds, including resistance selection and target identification.

Main Results:

• Identification of unique chemotypes exhibiting multi-stage or stage-specific activity.
• Discovery of structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, exemplified by JmjC inhibitor ML324 and SQ109.
• ML324 was shown to inhibit histone demethylation, leading to aberrant gene expression and gametocyte death.
• SQ109 resistance selection implicated the V-type H+-ATPase as a potential drug target.

Conclusions:

• The study provides a valuable dataset of compounds for potential antimalarial drug development.
• Identified compounds demonstrate efficacy against various Plasmodium parasite stages, including transmission stages.
• The findings highlight druggable targets, such as V-type H+-ATPase, applicable across multiple parasite life cycle stages.