Plasmodium falciparum DNA damage-inducible 1 protein (retroviral aspartyl protease) (PfDDI1)

Plasmodium falciparum DNA damage-inducible 1 protein (PfDDI1) is an essential aspartyl protease featuring a retroviral protease (RVP) domain and a ubiquitin-like (UBL) domain. It performs critical roles in the ubiquitin-proteasome system for protein degradation, removal of DNA-protein crosslinks, and maintaining parasite survival during all life stages. PfDDI1 depletion results in the accumulation of DNA-protein crosslinks, increased sensitivity to DNA-damaging agents and antimalarials, and impaired parasite growth, supporting its status as a validated therapeutic target. Its retroviral protease domain makes it susceptible to inhibition by HIV protease inhibitors (e.g., lopinavir), as well as artemisinin, which bind directly to the catalytic motif of PfDDI1. Knockdown of PfDDI1 not only impairs parasite survival but also confers immunity in murine models, highlighting its potential utility in vaccine development.

Other names

DNA damage-inducible 1 proteinPfDdi1Ddi1 retroviral proteaseRetropepsin-like protease

Inhibition by retroviral protease inhibitors (e.g., lopinavir) reduces parasite fitness and growth. Artemisinin binds directly to the conserved aspartic protease motif in PfDdi1, inhibiting its function and leading to parasite death. Knockdown or inhibition increases parasite sensitivity to DNA damage.