7ve0
Crystal Structure of Ritonavir bound Plasmepsin II (PMII) from Plasmodium falciparum
Structural highlights
FunctionPLM2_PLAF7 During the asexual blood stage, participates in initial cleavage of native host hemoglobin (Hb) resulting in Hb denaturation (PubMed:29943906). May cleave preferentially denatured hemoglobin that has been cleaved by PMI (By similarity). Digestion of host Hb is an essential step which provides the parasite with amino acids for protein synthesis, and regulates osmolarity (Probable).[UniProtKB:P46925][1] Publication Abstract from PubMedPlasmodium species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by Plasmodium parasites in the population co-infected with both HIV-1 and malaria. However, the mechanism of HIV-1 PIs in mitigating Plasmodium pathogenesis during malaria/HIV-1 co-infection is not fully understood. In this study we demonstrate that HIV-1 drugs ritonavir (RTV) and lopinavir (LPV) exhibit the highest inhibition activity against plasmepsin II (PMII) and plasmepsin X (PMX) of P. falciparum. Crystal structures of the complexes of PMII with both drugs have been determined. The inhibitors interact with PMII via multiple hydrogen bonding and hydrophobic interactions. The P4 moiety of RTV forms additional interactions compared to LPV and exhibits conformational flexibility in a large S4 pocket of PMII. Our study is also the first to report inhibition of P. falciparum PMX by RTV and the mode of binding of the drug to the PMX active site. Analysis of the crystal structures implies that PMs can accommodate bulkier groups of these inhibitors in their S4 binding pockets. Structurally similar active sites of different vacuolar and non-vacuolar PMs suggest the potential of HIV-1 PIs in targeting these enzymes with differential affinities. Our structural investigations and biochemical data emphasize PMs as crucial targets for repurposing HIV-1 PIs as antimalarial drugs. Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery.,Mishra V, Deshmukh A, Rathore I, Chakraborty S, Patankar S, Gustchina A, Wlodawer A, Yada RY, Bhaumik P Curr Res Struct Biol. 2024 Jan 17;7:100128. doi: 10.1016/j.crstbi.2024.100128. , eCollection 2024. PMID:38304146[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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