Hostname: page-component-848d4c4894-nr4z6 Total loading time: 0 Render date: 2024-05-15T02:29:48.925Z Has data issue: false hasContentIssue false
  • English
  • Français

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
Get access Rights & Permissions [Opens in a new window]

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
Check for updates
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

†

Present address: Evidence Action, Hanoi, Vietnam.

‡

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

References

REFERENCES

Acharya, P., Kumar, R. and Tatu, U. (2007). Chaperoning a cellular upheaval in malaria: heat shock proteins in Plasmodium falciparum . Molecular and Biochemical Parasitology 153, 85–94.CrossRefGoogle ScholarPubMed
Alag, R., Bharatham, N., Dong, A., Hills, T., Harikishore, A., Widjaja, A. A., Shochat, S. G., Hui, R. and Yoon, H. S. (2009). Crystallographic structure of the tetratricopeptide repeat domain of Plasmodium falciparum FKBP35 and its molecular interaction with Hsp90 C-terminal pentapeptide. Protein Science 18, 2115–2124. http://dx.doi.org/10.1002/pro.226 CrossRefGoogle ScholarPubMed
Bell, A. (2005). Antimalarial drug synergism and antagonism: mechanistic and clinical significance. FEMS Microbiology Letters 253, 171–184.Google Scholar
Bell, A., Wernli, B., and Franklin, R. M. (1994). Roles of peptidyl-prolyl cis-trans isomerase and calcineurin in the mechanisms of antimalarial action of cyclosporin A, FK506, and rapamycin. Biochemical Pharmacology 48, 495–503.Google Scholar
Bell, A., Monaghan, P. and Page, A. P. (2006). Peptidyl-prolyl cis–trans isomerases (immunophilins) and their roles in parasite biochemistry, host–parasite interaction and antiparasitic drug action. International Journal for Parasitology 36, 261–76.Google Scholar
Berriman, M. and Fairlamb, A. H. (1998). Detailed characterization of a cyclophilin from the human malaria parasite Plasmodium falciparum . Biochemical Journal 334, 437–445.Google Scholar
Bianchin, A., Allemand, F., Bell, A., Chubb, A. J. and Guichou, J. F. (2015). Two crystal structures of the FK506-binding domain of Plasmodium falciparum FKBP35 in complex with rapamycin at high resolution. Acta Crystallographica Series D: Biological Crystallography 71, 1319–1327. http://dx.doi.org/10.1107/S1399004715006239 Google Scholar
Bianchin, A., Chubb, A. and Bell, A. (2016). Immunophilins as possible drug targets in Apicomplexan parasites. In Comprehensive Analysis of Parasite Biology – from Metabolism to Drug Discovery (ed. Müller, S., Cerdan, R. and Radulescu, O.), pp. 193–212. Wiley VCH Verlag GmbH & Co. KGaA, Weinheim, Germany.Google Scholar
Bierer, B. E., Mattila, P. S., Standaert, R. F., Herzenberg, L. A., Burakoff, S. J., Crabtree, G. and Schreiber, S. L. (1990). Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proceedings of the National Academy of Sciences of the United States of America 87, 9231–9235.Google Scholar
Blackburn, E. A. and Walkinshaw, M. D. (2011). Targeting FKBP isoforms with small-molecule ligands. Current Opinion in Pharmacology 11, 365–371. http://dx.doi.org/10.1016/j.coph.2011.04.007 Google Scholar
Braun, P. D., Barglow, K. T., Lin, Y. M., Akompong, T., Briesewitz, R., Ray, G. T., Haldar, K. and Wandless, T. J. (2003). A bifunctional molecule that displays context-dependent cellular activity. Journal of the American Chemical Society 125, 7575–7580.Google Scholar
Cao, W. and Konsolaki, M. (2011). FKBP immunophilins and Alzheimer's disease: a chaperoned affair. Journal of Bioscience 36, 493–498.CrossRefGoogle ScholarPubMed
Cunningham, E., Drag, M., Kafarski, P. and Bell, A. (2008). Chemical target validation studies of aminopeptidase in malaria parasites using alpha-aminoalkylphosphonate and phosphonopeptide inhibitors. Antimicrobial Agents and Chemotherapy 52, 3221–3228. http://dx.doi.org/10.1128/AAC.01327-07 Google Scholar
Dobson, S., May, T., Berriman, M., Del Vecchio, C., Fairlamb, A. H., Chakrabarti, D. and Barik, S. (1999). Characterization of protein Ser/Thr phosphatases of the malaria parasite, Plasmodium falciparum: inhibition of the parasitic calcineurin by cyclophilin–cyclosporin complex. Molecular and Biochemical Parasitology 99, 167–181.Google Scholar
Fennell, B. J., Naughton, J. A., Dempsey, E. and Bell, A. (2006). Cellular and molecular actions of dinitroaniline and phosphorothioamidate herbicides on Plasmodium falciparum: tubulin as a specific antimalarial target. Molecular and Biochemical Parasitology 145, 226–238.CrossRefGoogle ScholarPubMed
Flannery, E. L., Chatterjee, A. K. and Winzeler, E. A. (2013). Antimalarial drug discovery – approaches and progress towards new medicines. Nature Reviews Microbiology 11, 849–862. http://dx.doi.org/10.1038/nrmicro3138 Google Scholar
Frausto, S. D., Lee, E. and Tang, H. (2013). Cyclophilins as modulators of viral replication. Viruses 11, 1684–1701. http://dx.doi.org/10.3390/v5071684 CrossRefGoogle Scholar
Gaali, S., Gopalakrishnan, R., Wang, Y., Kozany, C., Hausch, F. (2011). The chemical biology of immunophilin ligands. Current Medicinal Chemistry 18, 5355–5379.CrossRefGoogle ScholarPubMed
Galat, A. (2003). Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity–targets–functions. Current Topics in Medicinal Chemistry 3, 1315–1347.Google Scholar
Galat, A. and Bua, J. (2010). Molecular aspects of cyclophilins mediating therapeutic actions of their ligands. Cellular and Molecular Life Sciences 67, 3467–3488.Google Scholar
Gavigan, C. S., Machado, S. G., Dalton, J. P. and Bell, A. (2001). Analysis of antimalarial synergy between bestatin and endoprotease inhibitors using statistical response-surface modelling. Antimicrobial Agents and Chemotherapy 45, 3175–3181.Google Scholar
Gavigan, C. S., Kiely, S. P., Hirtzlin, J. and Bell, A. (2003). Cyclosporin-binding proteins of Plasmodium falciparum . International Journal for Parasitology 33, 987–996.Google Scholar
Gavigan, C. S., Shen, M., Machado, S. G. and Bell, A. (2007). Influence of the Plasmodium falciparum P-glycoprotein homologue 1 (pfmdr1 gene product) on the antimalarial action of cyclosporin. Journal of Antimicrobial Chemotherapy 59, 197–203.Google Scholar
Greco, W. R., Bravo, G. and Parsons, J. C. (1995). The search for synergy: a critical review from a response surface perspective. Pharmacological Reviews 47, 331–385.Google Scholar
Harikishore, A. and Yoon, H. S. (2015). Immunophilins: structures, mechanisms and ligands. Current Molecular Pharmacology 9, 37–47.Google Scholar
Harikishore, A., Leow, M. L., Niang, M., Rajan, S., Pasunooti, K. K., Preiser, P. R., Liu, X. and Yoon, H. S. (2013 a). Adamantyl derivative as a potent inhibitor of Plasmodium FK506 binding protein 35. ACS Medicinal Chemistry Letters 4, 1097–1101. http://dx.doi.org/10.1021/ml400306r Google Scholar
Harikishore, A., Niang, M., Rajan, S., Preiser, P. R. and Yoon, H. S. (2013 b). Small molecule Plasmodium FKBP35 inhibitor as a potential antimalaria agent. Scientific Reports 3, 2501. http://dx.doi.org/10.1038/srep02501.Google Scholar
Hirtzlin, J., Färber, P. M., Franklin, R. M. and Bell, A. (1995). Molecular and biochemical characterization of a Plasmodium falciparum cyclophilin containing a cleavable signal sequence. European Journal of Biochemistry 232, 765–772.Google Scholar
Juvvadi, P. R., Lee, S. C., Heitman, J. and Steinbach, W. J. (2016). Calcineurin in fungal virulence and drug resistance: prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach. Virulence Jun 20, 1–12 (E-pub) http://dx.doi.org/10.1080/21505594.2016.1201250 Google Scholar
Kotaka, M., Ye, H., Alag, R., Hu, G., Bozdech, Z., Preiser, P. R., Yoon, H. S. and Lescar, J. (2008). Crystal structure of the FK506 binding domain of Plasmodium falciparum FKBP35 in complex with FK506. Biochemistry 47, 5951–5961. http://dx.doi.org/10.1021/bi800004u Google Scholar
Kumar, R., Musiyenko, A., Oldenburg, A., Adams, B., Barik, S. (2004). Post-translational generation of constitutively active cores from larger phosphatases in the malaria parasite, Plasmodium falciparum: implications for proteomics. BMC Molecular Biology 5, 6.Google Scholar
Kumar, R., Adams, B., Musiyenko, A., Shulyayeva, O. and Barik, S. (2005). The FK506-binding protein of the malaria parasite, Plasmodium falciparum, is a FK506-sensitive chaperone with FK506-independent calcineurin-inhibitory activity. Molecular and Biochemical Parasitology 141, 163–173.Google Scholar
Lambros, C. and Vanderberg, J. P. (1979). Synchronization of Plasmodium falciparum erythrocytic stages in culture. Journal of Parasitology 65, 418–420.Google Scholar
Le Manach, C., Scheurer, C., Sax, S., Schleiferböck, S., Cabrera, D. G., Younis, Y., Paquet, T., Street, L., Smith, P., Ding, X. C., Waterson, D., Witty, M. J., Leroy, D., Chibale, K. and Wittlin, S. (2013). Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum . Malaria Journal 12, 424. http://dx.doi.org/10.1186/1475-2875-12-424 Google Scholar
Leneghan, D. and Bell, A. (2015). Immunophilin–protein interactions in Plasmodium falciparum . Parasitology 142, 1404–1414. http://dx.doi.org/10.1017/S0031182015000803 Google Scholar
Marín-Menéndez, A. and Bell, A. (2011). Overexpression, purification and assessment of cyclosporin binding of a family of cyclophilins and cyclophilin-like proteins of the human malarial parasite Plasmodium falciparum . Protein Expression and Purification 78, 225–234. http://dx.doi.org/10.1016/j.pep.2011.04.012 Google Scholar
Monaghan, P. and Bell, A. (2005). A Plasmodium falciparum FK506-binding protein (FKBP) with peptidyl-prolyl cis-trans isomerase and chaperone activities. Molecular and Biochemical Parasitology 139, 185–195.Google Scholar
Monaghan, P., Fardis, M., Revill, W. P. and Bell, A. (2005). Antimalarial effects of macrolactones related to FK520 (ascomycin) are independent of the immunosuppressive properties of the compounds. Journal of Infectious Diseases 191, 1342–1349.CrossRefGoogle ScholarPubMed
Paul, A. S., Saha, S., Engelberg, K., Jiang, R. H., Coleman, B. I., Kosber, A. L., Chen, C. T., Ganter, M., Espy, N., Gilberger, T. W., Gubbels, M. J. and Duraisingh, M. T. (2015). Parasite calcineurin regulates host cell recognition and attachment by Apicomplexans. Cell Host and Microbe 18, 49–60. http://dx.doi.org/10.1016/j.chom.2015.06.003 Google Scholar
Philip, N. and Waters, A. P. (2015). Conditional degradation of Plasmodium calcineurin reveals functions in parasite colonization of both host and vector. Cell Host and Microbe 18, 122–131. http://dx.doi.org/10.1016/j.chom.2015.05.018 Google Scholar
Reddy, G. R. (1995). Cloning and characterization of a Plasmodium falciparum cyclophilin gene that is stage-specifically expressed. Molecular and Biochemical Parasitology 73, 111–121.Google Scholar
Siekierka, J. J., Staruch, M. J., Hung, S. H. and Sigal, N. H. (1989). FK-506, a potent novel immunosuppressive agent, binds to a cytosolic protein which is distinct from the cyclosporin A-binding protein, cyclophilin. Journal of Immunology 143, 1580–1583.CrossRefGoogle ScholarPubMed
Singh, S., More, K. R. and Chitnis, C. E. (2014). Role of calcineurin and actin dynamics in regulated secretion of microneme proteins in Plasmodium falciparum merozoites during erythrocyte invasion. Cellular Microbiology 16, 50–63. http://dx.doi.org/10.1111/cmi.12177 Google Scholar
Yeh, P., Tschumi, A. I. and Kishony, R. (2006). Functional classification of drugs by properties of their pairwise interactions. Nature Genetics 38, 489–494.Google Scholar
Yoon, H. R., Kang, C. B., Chia, J., Tang, K. and Yoon, H. S. (2007). Expression, purification, and molecular characterization of Plasmodium falciparum FK506-binding protein 35 (PfFKBP35). Protein Expression and Purification 53, 179–185.Google Scholar
Zimmermann, G. R., Lehár, J. and Keith, C. T. (2007). Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discovery Today 12, 34–42.Google Scholar