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Mechanistic insights into non-immunosuppressive immunophilin ligands as potential antimalarial therapeutics
Malaria Journal volume 9, Article number: P60 (2010)
The immunosuppressive drug FK506 reveals an antimalarial activity. The mechanism of the drug action involves the molecular interaction with target proteins PfFKBP35 and PvFKBP35 from P. falciparum and P. vivax, respectively. Interestingly, non-immunosuppressive FK506 analogues also show antimalarial activities. This prompted us to attempt to develop potential small molecule antagonists that specifically target the parasite enzymes devoid of immunosuppressive activity. To this end, we have determined the three-dimensional structures of the FK506 binding domain (FKBD) of P. falciparum and P. vivax in unligand form and in complex with FK506.The structural studies reveal that the Plasmodium FKBPs have similar structural folds like the canonical FKBP folds (Figure 1 overleaf), providing mechanistic insights into PfFKBP35 and PvFKBP35 with possible routes for rational antimalarial drug design targeting the Plasmodium FKBPs.
Our structure-guided drug screening efforts resulted in an identification of novel adamantanyl-based-antimalarial compound named Supradamal (SRA). SRA exhibits a nanomolar inhibitory activity in both peptidylprolyl cis-trans isomerase (PPIase) assay and growth of P. falciparum cultured in human erythrocytes. In particular, SRA appears to inhibit the trophozoite development.
Alag A, Qureshi IA, Bharatham N, Shin J, Lescar J, Yoon HS: NMR and crystallographic structures of the FK506 binding domain of human malarial parasite Plasmodium vivax FKBP35. Protein Sci. 2010,
Kotaka M, Ye H, Alag R, Hu G, Bozdech Z, Preiser PR, Yoon HS, Lescar J: Crystal structure of the FK506 binding domain of Plasmodium falciparum FKBP35 in complex with FK506. Biochemistry. 2008, 47: 5951-61. 10.1021/bi800004u.
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Yoon, H.S., Alag, R., Kang, C. et al. Mechanistic insights into non-immunosuppressive immunophilin ligands as potential antimalarial therapeutics. Malar J 9, P60 (2010) doi:10.1186/1475-2875-9-S2-P60
- Antimalarial Drug
- Human Erythrocyte
- Mechanistic Insight
- Antimalarial Activity