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The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35

Published online by Cambridge University Press:  09 March 2017

PAUL MONAGHAN ,
DARREN B. LENEGHAN ,
WESLEY SHAW  and
ANGUS BELL Open the ORCID record for ANGUS BELL [Opens in a new window]
PAUL MONAGHAN
Affiliation:
Department of Microbiology, School of Genetics & Microbiology, Moyne Institute, Trinity College Dublin, Ireland
DARREN B. LENEGHAN
Affiliation:
Department of Microbiology, School of Genetics & Microbiology, Moyne Institute, Trinity College Dublin, Ireland
WESLEY SHAW
Affiliation:
Department of Microbiology, School of Genetics & Microbiology, Moyne Institute, Trinity College Dublin, Ireland
ANGUS BELL*
Affiliation:
Department of Microbiology, School of Genetics & Microbiology, Moyne Institute, Trinity College Dublin, Ireland
*
*Corresponding author: Institute of Cancer Research, 123 Old Brompton Rd., London SW7 3RP, UK. E-mail: angus.bell@icr.ac.uk
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Summary

FK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506–FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap –FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement of Plasmodium calcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of the Plasmodium falciparum FKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.

Keywords

malariaPlasmodiumantimalarialFK506rapamycinFKBPcalcineurindrug interaction
Type
Research Article
Information
Parasitology , Volume 144 , Issue 7 , June 2017 , pp. 869 - 876
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Copyright
Copyright © Cambridge University Press 2017 

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Footnotes

†

Present address: Evidence Action, Hanoi, Vietnam.

‡

Present address: Jenner Institute, ORCRB, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK.

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