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Mechanistic insights into non-immunosuppressive immunophilin ligands as potential antimalarial therapeutics

Clinical background

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.

Figure 1
figure 1

FK506 in complex with PvFKBD and ternary complex of FK506/PfFKBD/Calcineurin. (A) The electron density map of FK506 at the ligand binding site in PvFKBD. The residues near the FK506 are labeled and displayed as stick model in element colors. (B) Electrostatic surface representation of the residues near the FK506 binding sites in PvFKBD. Positive and negative charges are in blue and red, respectively. (C) Ternary complex model of FK506-bound PfFKBD and calcineurin. PfFKBD (yellow) was overlaid onto FKBP12 (pale cyan) of the FKBP12-FK506-calcineurin ternary complex in order to construct the ternary complex. FK506 is shown in sticks and calcineurin is shown in blue and cyan with its subunits A and B, respectively.


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.


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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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 (Suppl 2), P60 (2010).

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