DNA damage-inducible protein 1 protease (Plasmodium falciparum) (PfDdi1)

DNA damage-inducible protein 1 protease (PfDdi1) is an essential aspartyl protease and member of the A2 family that is unique to Plasmodium falciparum and closely related apicomplexan parasites[1][3]. The protein contains a ubiquitin-like (UBL) domain and a retroviral-protease (RVP) domain and is involved in degradation of polyubiquitinated proteins, functioning within the parasite’s ubiquitin-proteasome pathway[1][3][4]. PfDdi1 is required for parasite viability throughout the life cycle, coordinating cellular responses to protein and DNA damage by hydrolyzing polyubiquitinated substrates and contributing to removal of DNA-protein crosslinks[3][4]. Inhibition or depletion of PfDdi1 results in accumulation of damaged or ubiquitinated proteins, impaired parasite development, and sensitization to DNA-damaging agents and antimalarial drugs such as artemisinin[3][4]. PfDdi1 is a potential antimalarial drug target, as well as a candidate for whole-organism vaccine development due to its essential non-redundant role and immune-potentiating properties[3]. Its retroviral-protease-like activity also makes it susceptible to some HIV protease inhibitors, supporting the rationale for repurposing or designing inhibitors targeting the Ddi1 family in malaria and potentially related pathogens[3][6].

Other names

DNA damage-inducible protein 1PfDDI1Plasmodium falciparum DDI1Ddi1 protease

Inhibition of PfDdi1 blocks degradation of polyubiquitinated proteins, leading to accumulation of damaged proteins and increased parasite susceptibility to cell stress and antimalarial drugs[4] Artemisinin and HIV protease inhibitors act (at least in part) by inhibiting PfDdi1 enzymatic activity, thereby impairing the parasite’s ability to process protein and DNA damage[3][4]