Skip to main content

Heat shock protein 90 as a potential drug target against surra


Trypanosomiasis is caused by Trypanosoma species which affect both human and animal populations and pose a major threat to developing countries. The incidence of animal trypanosomiasis is on the rise. Surra is a type of animal trypanosomiasis, caused by Trypanosoma evansi, and has been included in priority list B of significant diseases by the World Organization of Animal Health (OIE). Control of surra has been a challenge due to the lack of effective drugs and vaccines and emergence of resistance towards existing drugs. Our laboratory has previously implicated Heat shock protein 90 (Hsp90) from protozoan parasites as a potential drug target and successfully demonstrated efficacy of an Hsp90 inhibitor in cell culture as well as a pre-clinical mouse model of trypanosomiasis. This article explores the role of Hsp90 in the Trypanosoma life cycle and its potential as a drug target. It appears plausible that the repertoire of Hsp90 inhibitors available in academia and industry may have value for treatment of surra and other animal trypanosomiasis.

Corresponding author
* Corresponding author: Department of Biochemistry, Indian Institute of Science, Bangalore-560012, India. E-mail:,
Hide All
Banumathy, G., Singh, V., Pavithra, S. R. and Tatu, U. (2003). Heat shock protein 90 function is essential for Plasmodium falciparum growth in human erythrocytes. Journal of Biological Chemistry 278, 1833618345. doi: 10.1074/jbc.M211309200.
Berger, B. J. and Fairlamb, A. H. (1994). Properties of melarsamine hydrochloride (Cymelarsan) in aqueous solution. Antimicrobial Agents and Chemotherapy 38, 12981302. doi: 10.1128/AAC.38.6.1298.
Brandt, G. E., Schmidt, M. D., Prisinzano, T. E. and Blagg, B. S. (2008). Gedunin, a novel hsp90 inhibitor: semisynthesis of derivatives and preliminary structure-activity relationships. Journal of Medicinal Chemistry 51, 64956502. doi: 10.1021/jm8007486.
Desquesnes, M., Bossard, G., Patrel, D., Herder, S., Patout, O., Lepetitcolin, E., Thevenon, S., Berthier, D., Pavlovic, D., Brugidou, R., Jacquiet, P., Schelcher, F., Faye, B., Touratier, L. and Cuny, G. (2008). First outbreak of Trypanosoma evansi in camels in metropolitan France. Veterinary Record 162, 750752. doi: 10.1136/vr.162.23.750.
Desquesnes, M., Holzmuller, P., Lai, D. H., Dargantes, A., Lun, Z. R. and Jittaplapong, S. (2013). Trypanosoma evansi and surra: a review and perspectives on origin, history, distribution, taxonomy, morphology, hosts, and pathogenic effects. BioMed Research International 2013, 194176. doi: 10.1155/2013/194176.
Dolgin, E. and Motluk, A. (2011). Heat shock and awe. Nature Medicine 17, 646649. doi: 10.1038/nm0611-646.
Donnelly, A. and Blagg, B. S. (2008). Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Current Medicinal Chemistry 15, 27022717. doi: 10.2174/092986708786242895.
Du, Y., Moulick, K., Rodina, A., Aguirre, J., Felts, S., Dingledine, R., Fu, H. and Chiosis, G. (2007). High-throughput screening fluorescence polarization assay for tumor-specific Hsp90. Journal of Biomolecular Screening 12, 915924. doi: 10.1177/1087057107306067.
Dutton, B. L., Kitson, R. R., Parry-Morris, S., Roe, S. M., Prodromou, C. and Moody, C. J. (2014). Synthesis of macrolactam analogues of radicicol and their binding to heat shock protein Hsp90. Organic and Biomolecular Chemistry 12, 13281340. doi: 10.1039/c3ob42211a.
El Rayah, I. E., Kaminsky, R., Schmid, C. and El Malik, K. H. (1999). Drug resistance in Sudanese Trypanosoma evansi . Veterinary Parasitology 80, 281287. doi: 10.1016/S0304-4017(98)00221-0.
Fevre, E. M., Coleman, P. G., Welburn, S. C. and Maudlin, I. (2004). Reanalyzing the 1900–1920 sleeping sickness epidemic in Uganda. Emerging Infectious Diseases 10, 567573. doi: 10.3201/eid1004.020626.
Gopalsamy, A., Shi, M., Golas, J., Vogan, E., Jacob, J., Johnson, M., Lee, F., Nilakantan, R., Petersen, R., Svenson, K., Chopra, R., Tam, M. S., Wen, Y., Ellingboe, J., Arndt, K. and Boschelli, F. (2008). Discovery of benzisoxazoles as potent inhibitors of chaperone heat shock protein 90. Journal of Medicinal Chemistry 51, 373375. doi: 10.1021/jm701385c.
Graefe, S. E., Wiesgigl, M., Gaworski, I., Macdonald, A. and Clos, J. (2002). Inhibition of HSP90 in Trypanosoma cruzi induces a stress response but no stage differentiation. Eukaryotic Cell 1, 936943. doi: 10.1128/EC.1.6.936-943.2002.
Janin, Y. L. (2005). Heat shock protein 90 inhibitors. A text book example of medicinal chemistry? Journal of Medicinal Chemistry 48, 75037512. doi: 10.1021/jm050759r.
Jones, C., Anderson, S., Singha, U. K. and Chaudhuri, M. (2008). Protein phosphatase 5 is required for Hsp90 function during proteotoxic stresses in Trypanosoma brucei . Parasitology Research 102, 835844. doi: 10.1007/s00436-007-0817-z.
Joshi, P. P., Shegokar, V. R., Powar, R. M., Herder, S., Katti, R., Salkar, H. R., Dani, V. S., Bhargava, A., Jannin, J. and Truc, P. (2005). Human trypanosomiasis caused by Trypanosoma evansi in India: the first case report. American Journal of Tropical Medicine and Hygiene 73, 491495.
Khandelwal, A., Hall, J. A. and Blagg, B. S. (2013). Synthesis and structure-activity relationships of EGCG analogues, a recently identified Hsp90 inhibitor. Journal of Organic Chemistry 78, 78597884. doi: 10.1021/jo401027r.
Kropf, S. P. and Sa, M. R. (2009). The discovery of Trypanosoma cruzi and Chagas disease (1908–1909): tropical medicine in Brazil. História, Ciências, Saúde-Manguinhos 16 (Suppl. 1), 1334.
Lathers, C. M. (2003). Challenges and opportunities in animal drug development: a regulatory perspective. Nature Reviews Drug Discovery 2, 915918. doi: 10.1038/nrd1229.
Liao, D. and Shen, J. (2010). Studies of quinapyramine-resistance of Trypanosoma brucei evansi in China. Acta Tropica 116, 173177. doi: 10.1016/j.actatropica.2010.08.016.
MacGregor, J. T. and Johnson, I. J. (1977). In vitro metabolic activation of ethidium bromide and other phenanthridinium compounds: mutagenic activity in Salmonella typhimurium . Mutation Research 48, 103107.
Marcu, M. G., Schulte, T. W. and Neckers, L. (2000). Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins. Journal of the National Cancer Institute 92, 242248. doi: 10.1093/jnci/92.3.242.
Meyer, K. J. and Shapiro, T. A. (2013). Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo . Journal of Infectious Diseases 208, 489499. doi: 10.1093/infdis/jit179.
Morgan, H. P., McNae, I. W., Nowicki, M. W., Zhong, W., Michels, P. A., Auld, D. S., Fothergill-Gilmore, L. A. and Walkinshaw, M. D. (2010). The trypanocidal drug suramin and other trypan blue mimetics are inhibitors of pyruvate kinases and bind to the adenosine site. Journal of Biological Chemistry 286, 3123231240. doi: 10.1074/jbc.M110.212613.
Nageshan, R. K., Roy, N., Hehl, A. B. and Tatu, U. (2011). Post-transcriptional repair of a split heat shock protein 90 gene by mRNA trans-splicing. Journal of Biological Chemistry 286, 71167122. doi: 10.1074/jbc.C110.208389.
Nakajima-Shimada, J., Hirota, Y. and Aoki, T. (1996). Inhibition of Trypanosoma cruzi growth in mammalian cells by purine and pyrimidine analogs. Antimicrobial Agents and Chemotherapy 40, 24552458.
Njiru, Z. K., Constantine, C. C., Ndung'u, J. M., Robertson, I., Okaye, S., Thompson, R. C. and Reid, S. A. (2004). Detection of Trypanosoma evansi in camels using PCR and CATT/T. evansi tests in Kenya. Veterinary Parasitology 124, 187199. doi: 10.1016/j.vetpar.2004.06.029.
OIE, W. O. f. A. H. (2012). OIE Terrestrial Manual 2012, Chapter 2.1.17. “Trypanosoma evansi Infections (Including Surra)”.
OIE (2013). Chapter 2.5.3. Dourine. OIE Terrestrial Manual.
Omoja, V. U., Anaga, A. O., Obidike, I. R., Ihedioha, T. E., Umeakuana, P. U., Mhomga, L. I., Asuzu, I. U. and Anika, S. M. (2011). The effects of combination of methanolic leaf extract of Azadirachta indica and diminazene diaceturate in the treatment of experimental Trypanosoma brucei brucei infection in rats. Asian Pacific Journal of Tropical Medicine 4, 337341. doi: 10.1016/S1995-7645(11)60099-0.
Pallavi, R., Roy, N., Nageshan, R. K., Talukdar, P., Pavithra, S. R., Reddy, R., Venketesh, S., Kumar, R., Gupta, A. K., Singh, R. K., Yadav, S. C. and Tatu, U. (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. Journal of Biological Chemistry 285, 3796437975. doi: 10.1074/jbc.M110.155317.
Pearl, L. H. and Prodromou, C. (2006). Structure and mechanism of the Hsp90 molecular chaperone machinery. Annual Review of Biochemistry 75, 271294. doi: 10.1146/annurev.biochem.75.103004.142738.
Peregrine, A. S. and Mamman, M. (1993). Pharmacology of diminazene: a review. Acta Tropica 54, 185203. doi: 10.1016/0001-706X(93)90092-P.
Pizarro, J. C., Hills, T., Senisterra, G., Wernimont, A. K., Mackenzie, C., Norcross, N. R., Ferguson, M. A., Wyatt, P. G., Gilbert, I. H. and Hui, R. (2013). Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. PLOS Neglected Tropical Diseases 7, e2492. doi: 10.1371/journal.pntd.0002492.
Ranjithkumar, M., Saravanan, B. C., Yadav, S. C., Kumar, R., Singh, R. and Dey, S. (2013). Neurological trypanosomiasis in quinapyramine sulfate-treated horses – a breach of the blood-brain barrier? Tropical Animal Health and Production 46, 371377. doi: 10.1007/s11250-013-0498-9.
Rochani, A. K., Singh, M. and Tatu, U. (2013). Heat shock protein 90 inhibitors as broad spectrum anti-infectives. Current Pharmaceutical Design 19, 377386. doi: 10.2174/1381612811306030377.
Samuni, Y., Ishii, H., Hyodo, F., Samuni, U., Krishna, M. C., Goldstein, S. and Mitchell, J. B. (2010). Reactive oxygen species mediate hepatotoxicity induced by the Hsp90 inhibitor geldanamycin and its analogs. Free Radical Biology and Medicine 48, 15591563. doi: 10.1016/j.freeradbiomed.2010.03.001.
Sharma, S. V., Agatsuma, T. and Nakano, H. (1998). Targeting of the protein chaperone, Hsp90, by the transformation suppressing agent, radicicol. Oncogene 16, 26392645. doi: 10.1038/sj.onc.1201790.
Siligardi, G., Hu, B., Panaretou, B., Piper, P. W., Pearl, L. H. and Prodromou, C. (2004). Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle. Journal of Biological Chemistry 279, 5198951998. doi: 10.1074/jbc.M410562200.
Singh, M., Shah, V. and Tatu, U. (2014). A novel C-terminal homologue of Aha1 co-chaperone binds to heat shock protein 90 and stimulates its ATPase activity in Entamoeba histolytica . Journal of Molecular Biology 426, 17861798. doi: 10.1016/j.jmb.2014.01.008.
Taipale, M., Jarosz, D. F. and Lindquist, S. (2010). Hsp90 at the hub of protein homeostasis: emerging mechanistic insights. Nature Reviews Molecular Cell Biology 11, 515528. doi: 10.1038/nrm2918.
Taldone, T., Sun, W. and Chiosis, G. (2009). Discovery and development of heat shock protein 90 inhibitors. Bioorganic and Medicinal Chemistry 17, 22252235. doi: 10.1016/j.bmc.2008.10.087.
Tuntasuvan, D., Jarabrum, W., Viseshakul, N., Mohkaew, K., Borisutsuwan, S., Theeraphan, A. and Kongkanjana, N. (2003). Chemotherapy of surra in horses and mules with diminazene aceturate. Veterinary Parasitology 110, 227233. doi: 10.1016/S0304-4017(02)00304-7.
Ul Hasan, M., Muhammad, G., Gutierrez, C., Iqbal, Z., Shakoor, A. and Jabbar, A. (2006). Prevalence of Trypanosoma evansi infection in equines and camels in the Punjab region, Pakistan. Annals of the New York Academy of Sciences 1081, 322324. doi: 10.1196/annals.1373.043.
Van der Ploeg, L. H., Giannini, S. H. and Cantor, C. R. (1985). Heat shock genes: regulatory role for differentiation in parasitic protozoa. Science 228, 14431446. doi: 10.1126/science.4012301.
Vigueira, P. A., Ray, S. S., Martin, B. A., Ligon, M. M. and Paul, K. S. (2012). Effects of the green tea catechin (-)-epigallocatechin gallate on Trypanosoma brucei . International Journal for Parasitology – Drugs and Drug Resistance 2, 225229. doi: 10.1016/j.ijpddr.2012.09.001.
Wang, M., Shen, G. and Blagg, B. S. (2006). Radanamycin, a macrocyclic chimera of radicicol and geldanamycin. Bioorganic and Medicinal Chemistry Letters 16, 24592462. doi: 10.1016/j.bmcl.2006.01.086.
Wells, E. A. (1984). Animal trypanosomiasis in South America. Preventive Veterinary Medicine 2, 3141. doi: 10.1016/0167-5877(84)90046-1.
Wiesgigl, M. and Clos, J. (2001). Heat shock protein 90 homeostasis controls stage differentiation in Leishmania donovani . Molecular Biology of the Cell 12, 33073316. doi: 10.1091/mbc.12.11.3307.
Yin, Z., Henry, E. C. and Gasiewicz, T. A. (2009). (-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor. Biochemistry 48, 336345. doi: 10.1021/bi801637q.
Zweygarth, E. and Kaminsky, R. (1990). Evaluation of an arsenical compound (RM 110, mel Cy, Cymelarsan) against susceptible and drug-resistant Trypanosoma brucei brucei and T. b. evansi . Tropical Medicine and Parasitology 41, 208212.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

  • ISSN: 0031-1820
  • EISSN: 1469-8161
  • URL: /core/journals/parasitology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 3
Total number of PDF views: 21 *
Loading metrics...

Abstract views

Total abstract views: 175 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st March 2018. This data will be updated every 24 hours.