Volume 9 Supplement 2

Parasite to Prevention: Advances in the understanding of malaria

Open Access

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

  • Ho Sup Yoon1,
  • Reema Alag1,
  • Congbao Kang1,
  • Hong Ye1,
  • Masayo Kotaka1,
  • Insaf A Qureshi1,
  • Nagakumar Bharatham1,
  • Joon Shin1,
  • Zbynek Bozdech1,
  • Peter Preiser1 and
  • Julien Lescar1
Malaria Journal20109(Suppl 2):P60

https://doi.org/10.1186/1475-2875-9-S2-P60

Published: 20 October 2010

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

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.

Conclusion

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.

Authors’ Affiliations

(1)
School of Biological Sciences, Nanyang Technological University

References

  1. 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,Google Scholar
  2. 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.View ArticlePubMedGoogle Scholar

Copyright

© Yoon et al; licensee BioMed Central Ltd. 2010

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 (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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