Plasmodium falciparum DNA damage-inducible protein 1 (PfDdi1)

Plasmodium falciparum DNA damage-inducible protein 1 (PfDdi1) is an essential retropepsin (A2 family aspartic protease) that serves as a critical component of the parasite's ubiquitin-proteasome system (UPS) and unfolded protein response (UPR) (Onchieku et al., 2021; Arora et al., 2023). It functions as a proteasome shuttle protein, facilitating the degradation of polyubiquitinated substrates and the repair of DNA-protein crosslinks (DPCs) (Arora et al., 2023; Oduro-Kwatenga et al., 2025). PfDdi1 is indispensable for the survival and development of the malaria parasite across its life cycle stages (Arora et al., 2023). Recent research has identified PfDdi1 as a primary target of artemisinin and its derivatives, which inhibit its proteolytic activity and lead to the toxic accumulation of damaged proteins and DNA (Onchieku et al., 2021; Oduro-Kwatenga et al., 2025). The inhibition of PfDdi1 results in the accumulation of toxic protein aggregates and unrepaired DNA damage, which are lethal to the parasite (Onchieku et al., 2021). Furthermore, its retroviral-like protease (RVP) domain makes it a potential target for HIV protease inhibitors like lopinavir, offering a novel avenue for antimalarial drug development and combination therapies to combat drug-resistant malaria (Arora et al., 2023; UniProt Q8IM03). This target is particularly attractive due to its essentiality and the presence of a unique protease fold that may allow for selective inhibition over human homologs (Onchieku et al., 2021).

Other names

PfDDI1DNA damage-inducible protein 1Proteasome shuttle proteinRetropepsinRetroviral-like aspartic proteaseA2 family aspartic protease

Inhibition of PfDdi1 protease activity leads to the accumulation of polyubiquitinated proteins and DNA-protein crosslinks, causing cellular toxicity and parasite death.