Parasites constitute one of the biggest threats seen to global health; however, a North American, San Diego dominant, research group recently discovered a potential anti-parasitic target. Using bioinformatics, the team found that disrupting the natural endoplasmic reticulum associated degradation (ERAD) pathway of plasmodium falciparum, a malaria parasite, proved lethal.
ERAD is a housekeeping mechanism of mammalian and parasitic cells, which works to break down mis-folded or broken proteins to prevent them from harming the host. In parasitic agents such as those causing malaria, toxoplasmosis, trypanosomiasis, and leishmaniasis, the ERAD system is more simple by nearly 60% than the mammalian parallel. Mis-folding of proteins is a common occurrence when the ER becomes stressed. Further analysis highlighted a key component, signal peptide peptidase (SPP), of the ERAD system. Because of the simplicity of the protozoan pathogens’ ERAD system, the loss of function of SPP would result in no breakdown of mis-folded proteins and dangerous nano-junk floating around inside the cell.
The team used this as a point of analysis. Experiments were done with SPP inhibitors in human and parasite cells to test efficacy in stopping the ERAD system. To do this, stress was forced onto the ER using thapsigarian in both cell types. Afterward, SPP inhibitors were introduced. Therefore, mis-folded proteins were forced out and ERAD could not degrade them because SPP was being inhibited. This caused an increase in bad protein formation without proper breakdown in parasitic cells, proving lethal. However, SPP inhibitors showed no toxicity in human cells.
Because of the inherent simplicity of the parasitic ERAD pathway, inhibition of the key component SPP proved effective in killing p. falciparum cells. This is similar to allowing weeds to grow in a garden. If the person responsible for killing the weeds is removed, the garden gets taken over by bad greenery and eventually dies.
SPP inhibitors are potent against a variety of pathogenic protozoan parasites and thus have potential to be targets for future anti-parasitic drugs.
Michael B. Harbut, Bhumit A. Patel, Bryan K. S. Yeung, Case W. McNamara, A. Taylor Bright, Jaime Ballard, Frantisek Supek, Todd E. Golde, Elizabeth A. Winzeler, Thierry T. Diagana, and Doron C. Greenbaum. 2012. Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design. PNAS.