Antimalarial resistance threatens malaria control, necessitating new therapeutics with novel targets. Plasmodium parasite egress from human erythrocytes and invasion of new host cells causes clinical manifestations of malaria, while transmission to the mosquito vector drives ongoing disease burden.
All essential biological processes within the parasite critically rely on the correct manufacturing of protein machinery to complete the lifecycle across both the human and mosquito host. Egress, invasion, and transmission are all underpinned by a repertoire of highly folded and disulphide-bonded proteins.
Protein disulphide isomerases (PDIs) are established eukaryotic protein folding chaperones and mediators of disulphide bonding. The primary malaria parasite, P. falciparum, possesses four highly conserved PDIs. Previous work has demonstrated essentiality of PDI-Trans in transmission and its vulnerability to chemical inhibition.
We now show that PDI-Trans knockdown also perturbs folding of essential egress and invasion proteins, and treatment with repurposed PDI inhibitors recapitulates this effect. We have generated compounds that prevent Plasmodium invasion/egress, transmission, and growth across multiple clinically relevant species with single digit nanomolar potency and irresistibility in erythrocytic stages.
With an established relationship between highly conserved PDIs and integral processes of egress, invasion, and transmission in Plasmodium, repurposing existing PDI inhibitors may offer an expedited and novel means of eliminating malaria parasites through dual-stage pan-species activity.