Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes

Area of Science:

• Malariology
• Structural Biology
• Drug Discovery

Background:

• Plasmepsin V is a vital aspartyl protease in malaria parasites.
• It plays a critical role in exporting effector proteins into infected erythrocytes.
• Plasmepsin V is a key drug target for Plasmodium falciparum and Plasmodium vivax.

Purpose of the Study:

• To develop a potent inhibitor of Plasmepsin V.
• To elucidate the structural basis of Plasmepsin V inhibition and substrate specificity.

Main Methods:

• Development of WEHI-842, a Plasmepsin V inhibitor mimicking the Plasmodium export element (PEXEL).
• Biochemical assays to determine inhibitor potency (IC50).
• X-ray crystallography to determine the structure of Plasmepsin V in complex with WEHI-842.

Main Results:

• WEHI-842 demonstrated potent inhibition of recombinant Plasmepsin V (IC50 = 0.2 nM).
• WEHI-842 effectively blocked protein export and inhibited parasite growth.
• The crystal structure revealed a plant-like fold and a malaria-specific helix-turn-helix motif crucial for substrate binding.

Conclusions:

• WEHI-842 is a highly effective Plasmepsin V inhibitor with therapeutic potential.
• The determined structure provides insights into Plasmepsin V function and substrate recognition.
• This work advances the development of novel antimalarial drugs targeting essential parasite processes.