Heat Shock Proteins as Targets for Novel Anti-Malarial Drugs

Chapter

Abstract

Molecular chaperones or heat shock proteins are involved in diverse biological processes and play an important role in maintaining cellular homeostasis. Thus, inhibiting their function can be detrimental to cell survival. It has been well established that elaborate involvement of heat shock proteins is required during the process of malaria pathogenesis. Hence, heat shock proteins serve as potential drug targets against malaria. The emergence of drug resistance in Plasmodium falciparum against existing anti-malarial drugs has created a pressing need for the identification of novel drug targets. Multiple strategies have been undertaken in this regard which involve target based drug discovery, identifying novel anti-malarial natural compounds, chemically modifying existing drugs or repurposing drugs used for other diseases. This chapter provides a comprehensive overview of the inhibitors of Hsp90 and Hsp70-40 molecular chaperone system tested for efficacy in Plasmodium falciparum. These compounds belong to diverse chemical families and are of both natural and synthetic origin. Naturally occurring napthoquinones and synthetic pyrimidinones target PfHsp70 function while geldanamycin, acrisorcin, APPA and harmine are natural compounds that inhibit PfHsp90 function. Some of these compounds like geldanamycin and its derivative 17-AAG have been also tested in the mouse model of malaria and have been found to be very effective. Overall, heat shock protein inhibitors not only provide us with a new avenue to tackle malaria but also shed light on novel features of parasite’s biology.

Keywords

Hsp90 Hsp70 Anti-malarial Geldanamycin Pyrimidinone Napthoquinone 

References

  1. Acharya P, Chaubey S, Grover M, Tatu U (2012) An exported heat shock protein associates with pathogenesis-related knobs in Plasmodium falciparum infected erythrocytes. PLoS One 7(9):e44605PubMedCrossRefGoogle Scholar
  2. Acharya P, Kumar R, Tatu U (2007) chaperoning a cellular upheaver in malaria: heat shock proteins in Plasmodium faliciprum. Mol Biochem Parasitol 153: 85-94Google Scholar
  3. Acharya P, Pallavi R, Chandran S, Chakravarti H, Middha S et al (2009) A glimpse into the clinical proteome of Plasmodium falciparum and Plasmodium vivax. Proteomics Clin Appl 3:1314–1325PubMedCrossRefGoogle Scholar
  4. Banumathy G, Singh V, Pavithra SR, Tatu U (2003) Heat shock protein 90 function is essential for Plasmodium falciparum growth in human erythrocytes. J Biol Chem 278:18336–18345PubMedCrossRefGoogle Scholar
  5. Barrott JJ, Haystead TA (2013) Hsp90 an unlikely ally in the war on cancer. FEBS J 280:1381–1396PubMedCrossRefGoogle Scholar
  6. Bonifazi EL, Ríos-Luci C, León LG, Burton G, Pardón JM, Misico RI (2010) Antiproliferative activity of synthetic naphthoquinones related to lapachol. First synthesis of 5-hydroxylapachol. Bioorg Med Chem 18:2621–2630PubMedCrossRefGoogle Scholar
  7. Botha M, Pesce ER, Blatch GL (2007) The Hsp40 proteins of Plasmodium falciparum and other apicomplexa: regulating chaperone power in the parasite and the host. Int J Biochem Cell Biol 39:1783–1803CrossRefGoogle Scholar
  8. Botha M, Chiang AN, Needham PG, Stephens LL, Hoppe HC et al (2011) Plasmodium falciparum encodes a single cytosolic type I Hsp40 that functionally interacts with Hsp70 and is upregulated by heat shock. Cell Stress Chaperones 16:389–401PubMedCrossRefGoogle Scholar
  9. Chiang AN, Valderramos JC, Balachandran R, Chovatiya RJ, Mead BP et al (2009) Select pyrimidinones inhibit the propagation of the malarial parasite Plasmodium falciparum. Bioorg Med Chem 17:1527–1533PubMedCrossRefGoogle Scholar
  10. Chua CS, Low H, Lehming N, Sim TS (2011) Molecular analysis of Plasmodium falciparum co-chaperone Aha1 supports its interaction with and regulation of Hsp90 in the malaria parasite. Int J Biochem Cell Biol 44:233–245PubMedCrossRefGoogle Scholar
  11. Cockburn IL, Pesce ER, Pryzborski JM, Davies-Coleman MT, Clark PG et al (2011) Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1. Biol Chem 392:431–438PubMedCrossRefGoogle Scholar
  12. Corbett KD, Berger JM (2010) Structure of the ATP-binding domain of Plasmodium falciparum Hsp90. Proteins 78:2738–2744PubMedCrossRefGoogle Scholar
  13. Daily JP, Scanfeld D, Pochet N, Le Roch K, Plouffe D et al (2007) Distinct physiological states of Plasmodium falciparum in malaria-infected patients. Nature 450:1091–1095PubMedCrossRefGoogle Scholar
  14. DeBoer C, Meulman PA, Wnuk RJ, Peterson DH (1970) Geldanamycin, a new antibiotic. J Antibiot (Tokyo) 23:442–447PubMedCrossRefGoogle Scholar
  15. DeBoer C, Dietz A (1976) The description and antibiotic production of Streptomyces hygroscopicus var. Geldanus. J Antibiot (Tokyo) 29:1182–1188Google Scholar
  16. de Koning-Ward TF, Gilson PR, Boddey JA, Rug M, Smith BJ et al (2009) A newly discovered protein export machine in malaria parasites. Nature 459:945–949PubMedCrossRefGoogle Scholar
  17. Graefe SE, Wiesgigl M, Gaworski I, Macdonald A, Clos J (2002) Inhibition of HSP90 in Trypanosoma cruzi induces a stress response but no stage differentiation. Eukaryot Cell 1:936–943PubMedCrossRefGoogle Scholar
  18. Grem JL, Morrison G, Guo XD, Agnew E, Takimoto CH et al (2005) Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 23:1885–1893PubMedCrossRefGoogle Scholar
  19. Grover M, Chaubey S, Ranade S, Tatu U (2013) Identification of an exported heat shock protein in Plasmodium falciparum. Parasite 20:2PubMedCrossRefGoogle Scholar
  20. Keyzers RA, Gray CA, Schleyer MH, Whibley CE, Hendricks DT, Davies-Coleman MT (2006) Malonganenones A–C, novel tetraprenylated alkaloids from the Mozambique gorgonian Leptogorgia gilchristi. Tetrahedron 62:2200–2206CrossRefGoogle Scholar
  21. Kitson RRA, Moody CJ (2013) Learning from Nature: Advances in Geldanamycin- and Radicicol-based inhibitors of Hsp90. J Org Chem 78:5117–5141 . doi: 10.1021/jo4002849Google Scholar
  22. Koulov AV, LaPointe P, Lu B, Razvi A, Coppinger J et al (2010) Biological and structural basis for Aha1regulation of Hsp90 ATPase activity in maintaining proteostasis in the human disease cystic fibrosis. Mol Biol Cell 21:871–884PubMedCrossRefGoogle Scholar
  23. Kulzer S, Rug M, Brinkmann K, Ping C, Cowman A et al (2010) Parasite-encoded Hsp40 proteins define novel mobile structures in the cytosol of the P. falciparum- infected erythrocyte. Cell Microbiol 12:1398–1420PubMedCrossRefGoogle Scholar
  24. Külzer S, Charnaud S, Dagan T, Riedel J, Mandal P, Pesce ER (2012) Plasmodium falciparum-encoded exported hsp70/hsp40 chaperone/co-chaperone complexes within the host erythrocyte. Cell Microbiol 14:1784–1795PubMedCrossRefGoogle Scholar
  25. Kumar R, Musiyenko A, Barik S (2003) The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin. Malar J 2:30PubMedCrossRefGoogle Scholar
  26. Kumar R, Musiyenko A, Barik S (2005) Plasmodium falciparum calcineurin and its association with heat shock protein 90: mechanisms for the antimalarial activity of cyclosporin A and synergism with geldanamycin. Mol Biochem Parasitol 141:29–37PubMedCrossRefGoogle Scholar
  27. Kumar R, Pavithra SR, Tatu U (2007) Three-dimensional structure of heat shock protein 90 from Plasmodium falciparum: molecular modelling approach to rational drug design against malaria. J Biosci 32:531–536PubMedCrossRefGoogle Scholar
  28. Li Z, Menoret A, Srivastava P (2002) Roles of heat-shock proteins in antigen presentation and cross-presentation. Curr Opin Immunol 14:45–51PubMedCrossRefGoogle Scholar
  29. Maier AG, Rug M, O’Neill MT, Brown M, Chakravorty S et al (2008) Exported proteins required for virulence and rigidity of Plasmodium falciparum infected human erythrocytes. Cell 134:48–61PubMedCrossRefGoogle Scholar
  30. Mout R, Xu ZD, Wolf AK, Jo Davisson V, Jarori GK (2012) Anti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoelii. Malar J 11:54PubMedCrossRefGoogle Scholar
  31. Muralidharan V, Oksman A, Pal P, Lindquist S, Goldberg DE (2012) Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeat-rich parasite proteome during malarial fevers. Nat Commun 3:1310PubMedCrossRefGoogle Scholar
  32. Nageshan RK, Roy N, Hehl AB, Tatu U (2011) Post-transcriptional repair of a split heat shock protein 90 gene by mRNA trans-splicing. J Biol Chem 286:7116–7122PubMedCrossRefGoogle Scholar
  33. Njunge JM, Ludewig MH, Boshoff A, Pesce ER, Blatch GL (2013) Hsp70s and J proteins of Plasmodium parasites infecting rodents and primates: structure, function, clinical relevance, and drug targets. Curr Pharm Des 19:387–403PubMedCrossRefGoogle Scholar
  34. Pallavi R, Acharya P, Chandran S, Daily JP, Tatu U (2010) Chaperone expression profiles correlate with distinct physiological states of Plasmodium falciparum in malaria patients. Malar J 9:236PubMedCrossRefGoogle Scholar
  35. Pallavi R, Roy N, Nageshan RK, Talukdar P, Pavithra SR et al (2010) Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug. J Biol Chem 285:37964–37975PubMedCrossRefGoogle Scholar
  36. Pavithra SR, Banumathy G, Joy O, Singh V, Tatu U (2004) Recurrent fever promotes Plasmodium falciparum development in human erythrocytes. J Biol Chem 279:46692–46699PubMedCrossRefGoogle Scholar
  37. Pavithra SR, Kumar R, Tatu U (2007) Systems analysis of chaperone networks in the malarial parasite Plasmodium falciparum. PLoS Comput Biol 3:1701–1715PubMedCrossRefGoogle Scholar
  38. Pérez-Sacau E, Estévez-Braun A, Ravelo AG, Yapu DG, Turba AG (2005) Antiplasmodial activity of naphthoquinones related to lapachol and b-lapachone. Chem Biodevers 2:264–274CrossRefGoogle Scholar
  39. Ramya TN, Karmodiya K, Surolia A, Surolia N (2007) 15-deoxyspergualin primarily targets the trafficking of apicoplast proteins in Plasmodium falciparum. J Biol Chem 282:6388–6397PubMedCrossRefGoogle Scholar
  40. Retzlaff M, Hagn F, Mitschke L, Hessling M, Gugel F et al (2010) Asymmetric activation of the Hsp90 dimer by its cochaperone aha1. Mol Cell 37:344–354 . doi: 10.1016/j.molcel.2010.01.006PubMedCrossRefGoogle Scholar
  41. Rochani AK, Singh M, Tatu U (2013) Heat shock protein 90 inhibitors as broad spectrum anti-infectives. Curr Pharm Des 19:377–386PubMedCrossRefGoogle Scholar
  42. Schulte TW, Akinaga S, Soga S, Sullivan W, Stensgard B et al (1998) Antibiotic Radicicol binds to the N-terminal domain of Hsp90 and shares important biological activities with geldanamycin. Cell Stress Chaperones 3:100–108PubMedCrossRefGoogle Scholar
  43. Shahinas D, Liang M, Datti A, Pillai DR (2010) A repurposing strategy identifies novel synergistic inhibitors of Plasmodium falciparum heat shock protein 90. J Med Chem 13:3552–3557CrossRefGoogle Scholar
  44. Shahinas D, MacMullin G, Benedict C, Crandall I, Pillai DR (2012) Harmine is a potent antimalarial targeting Hsp90 and synergizes with chloroquin and artemisinin. Antimicrob Agents Chemother 56:4207–4213PubMedCrossRefGoogle Scholar
  45. Shonhai A, Boshoff A, Blatch GL (2007) The structural and functional diversity of Hsp70 proteins from Plasmodium falciparum. Protein Sci 16:1803–1818PubMedCrossRefGoogle Scholar
  46. Shonhai A, Botha M, De Beer TJ, Boshoff A, Blatch GL (2008) Structure-function study of a Plasmodium falciparum Hsp70 using three dimensional modelling and in vitro analyses. Protein Pept Lett 15:1117–1125PubMedCrossRefGoogle Scholar
  47. Singh GP, Chandra BR, Bhattacharya A, Akhouri RR, Singh SK et al (2004) Hyper-expansion of asparagines correlates with an abundance of proteins with prion-like domains in Plasmodium falciparum. Mol Biochem Parasitol 137:307–319PubMedCrossRefGoogle Scholar
  48. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP (1997) Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89:239–250PubMedCrossRefGoogle Scholar
  49. Supko JG, Hickman RL, Grever MR, Malspeis L (1995) Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 36:305–315PubMedCrossRefGoogle Scholar
  50. Taipale M, Jarosz DF, Lindquist S (2010) Hsp90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11:515–528PubMedCrossRefGoogle Scholar
  51. Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA 91:8324–8328PubMedCrossRefGoogle Scholar
  52. Wiesgigl M, Clos J (2001) Heat shock protein 90 homeostasis controls stage differentiation in Leishmania donovani. Mol Biol Cell 12:3307–3316PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of BiochemistryIndian Institute of ScienceBangaloreIndia

Personalised recommendations