Pharmaceutical Research

, 36:27 | Cite as

High Throughput and Computational Repurposing for Neglected Diseases

  • Helen W. HernandezEmail author
  • Melinda Soeung
  • Kimberley M. Zorn
  • Norah Ashoura
  • Melina Mottin
  • Carolina Horta Andrade
  • Conor R. Caffrey
  • Jair Lage de Siqueira-Neto
  • Sean EkinsEmail author
Expert Review



Neglected tropical diseases (NTDs) represent are a heterogeneous group of communicable diseases that are found within the poorest populations of the world. There are 23 NTDs that have been prioritized by the World Health Organization, which are endemic in 149 countries and affect more than 1.4 billion people, costing these developing economies billions of dollars annually. The NTDs result from four different causative pathogens: protozoa, bacteria, helminth and virus. The majority of the diseases lack effective treatments. Therefore, new therapeutics for NTDs are desperately needed.


We describe various high throughput screening and computational approaches that have been performed in recent years. We have collated the molecules identified in these studies and calculated molecular properties.


Numerous global repurposing efforts have yielded some promising compounds for various neglected tropical diseases. These compounds when analyzed as one would expect appear drug-like. Several large datasets are also now in the public domain and this enables machine learning models to be constructed that then facilitate the discovery of new molecules for these pathogens.


In the space of a few years many groups have either performed experimental or computational repurposing high throughput screens against neglected diseases. These have identified compounds which in many cases are already approved drugs. Such approaches perhaps offer a more efficient way to develop treatments which are generally not a focus for global pharmaceutical companies because of the economics or the lack of a viable market. Other diseases could perhaps benefit from these repurposing approaches.


dengue ebola echinococcosis elephantiasis high throughput screening kinetoplastids lymphatic filariasis neglected tropical diseases onchocerciasis repurposing schistosoma zika 


Acknowledgments and Disclosures

This work was supported by Award Numbers 1R43GM122196-01 and R44GM122196-02A1 “Centralized assay datasets for modelling support of small drug discovery organizations” from NIH/ NIGMS. 1UH2TR002084-01 “Repurposing pyronaridine as a treatment for Chagas disease” from NIH/ NCATS 1R21TR001718-01 “Repurposing pyronaridine as a treatment for the Ebola virus” from NIH / NCATS. MM thanks the support of the Brazilian CNPq/FAPEG DCR (grant 300508/2017-4). We are very grateful for our many collaborators and colleagues who contributed to the various efforts referenced herein. HWH is a Managing Member of KAL Research Initiatives, LLC. KMZ is an employee and SE is an employee and owner of Collaborations Pharmaceuticals, Inc.

Supplementary material

11095_2018_2558_MOESM1_ESM.docx (89 kb)
ESM 1 (DOCX 88 kb)
11095_2018_2558_MOESM2_ESM.sdf (2.6 mb)
ESM 2 (SDF 2684 kb)


  1. 1.
    Kotz J. Phenotypic screening, take two. SciBX. 2012;5:15.Google Scholar
  2. 2.
    Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007;6(1):29–40.PubMedGoogle Scholar
  3. 3.
    Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov. 2011;10(7):507–19.PubMedGoogle Scholar
  4. 4.
    Hotez PJ, Molyneux DH, Fenwick A, Kumaresan J, Sachs SE, Sachs JD, et al. Control of neglected tropical diseases. N Engl J Med. 2007;357(10):1018–27.Google Scholar
  5. 5.
    WHO. Neglected tropical diseases. Available from:
  6. 6.
    Hotez PJ, Pecoul B. "Manifesto" for advancing the control and elimination of neglected tropical diseases. PLoS Negl Trop Dis. 2010;4(5):e718.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ, Davis PH, et al. Chemical genetics of Plasmodium falciparum. Nature. 2010;465(7296):311–5.Google Scholar
  8. 8.
    Ribeiro I, Sevcsik AM, Alves F, Diap G, Don R, Harhay MO, et al. New, improved treatments for Chagas disease: from the R&D pipeline to the patients. PLoS Negl Trop Dis. 2009;3(7):e484.Google Scholar
  9. 9.
    Bettiol E, Samanovic M, Murkin AS, Raper J, Buckner F, Rodriguez A. Identification of three classes of heteroaromatic compounds with activity against intracellular Trypanosoma cruzi by chemical library screening. PLoS Negl Trop Dis. 2009;3(2):e384.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Ponder EL, Freundlich JS, Sarker M, Ekins S. Computational models for neglected diseases: gaps and opportunities. Pharm Res. 2014;31(2):271–7.PubMedGoogle Scholar
  11. 11.
    FDA. Tropical Disease Priority Review Vouchers Guidance for Industry. Available from:
  12. 12.
    Berman J, Radhakrishna T. The Tropical Disease Priority Review Voucher: A Game-Changer for Tropical Disease Products. Am J Trop Med Hyg. 2017;96(1):11–3.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Ridley DB. Priorities for the Priority Review Voucher. Am J Trop Med Hyg. 2017;96(1):14–5.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Gaffney A, Mezher M, Brennan Z. Regulatory Explainer: Everything You Need to Know About FDA’s Priority Review Vouchers Available from:
  15. 15.
    Boguski MS, Mandl KD, Sukhatme VP. Drug discovery. Repurposing with a difference. Science. 2009;324(5933):1394–5.PubMedGoogle Scholar
  16. 16.
    Uliana SR, Barcinski MA. Repurposing for neglected diseases. Science. 2009;326(5955):935 author reply 935.PubMedGoogle Scholar
  17. 17.
    Huang R, Southall N, Wang Y, Yasgar A, Shinn P, Jadhav A, et al. The NCGC Pharmaceutical Collection: A Comprehensive Resource of Clinically Approved Drugs Enabling Repurposing and Chemical Genomics. Sci Transl Med. 2011;3(80):80ps16.Google Scholar
  18. 18.
    Kinnings SL, Liu N, Tonge PJ, Jackson RM, Xie L, Bourne PE. A machine learning-based method to improve docking scoring functions and its application to drug repurposing. J Chem Inf Model. 2011;51(2):408–19.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Oprea TI, Mestres J. Drug Repurposing: Far Beyond New Targets for Old Drugs. AAPS J. 2012;14:759–63.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Blatt J, Farag S, Corey SJ, Sarrimanolis Z, Muratov E, Fourches D, et al. Expanding the scope of drug repurposing in pediatrics: The Children's Pharmacy Collaborative. Drug Discov Today. 2014;19:1696–8.Google Scholar
  21. 21.
    Martorana A, Perricone U, Lauria A. The Repurposing of Old Drugs or Unsuccessful Lead Compounds by in Silico Approaches: New Advances and Perspectives. Curr Top Med Chem. 2016;16(19):2088–106.PubMedGoogle Scholar
  22. 22.
    Baker NC, Ekins S, Williams AJ, Tropsha A. A bibliometric review of drug repurposing. Drug Discov Today. 2018;23(3):661–72.PubMedGoogle Scholar
  23. 23.
    Dudley JT, Deshpande T, Butte AJ. Exploiting drug-disease relationships for computational drug repositioning. Brief Bioinform. 2011;12(4):303–11.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Dimasi JA. New drug development in the United States from 1963 to 1999. Clin Pharmacol Ther. 2001;69(5):286–96.PubMedGoogle Scholar
  25. 25.
    Li T, Ziniel PD, He PQ, Kommer VP, Crowther GJ, He M, et al. High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis. Infect Dis Poverty. 2015;4:40.Google Scholar
  26. 26.
    Khare S, Nagle AS, Biggart A, Lai YH, Liang F, Davis LC, et al. Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature. 2016;537(7619):229–33.Google Scholar
  27. 27.
    Diaz R, Luengo-Arratta SA, Seixas JD, Amata E, Devine W, Cordon-Obras C, et al. Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign. PLoS Negl Trop Dis. 2014;8(10):e3253.Google Scholar
  28. 28.
    Mansour NR, Paveley R, Gardner JM, Bell AS, Parkinson T, Bickle Q. High Throughput Screening Identifies Novel Lead Compounds with Activity against Larval, Juvenile and Adult Schistosoma mansoni. PLoS Negl Trop Dis. 2016;10(4):e0004659.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Cole ST. Tuberculosis drug discovery needs public-private consortia. Drug Discov Today. 2016;22:477–8.PubMedGoogle Scholar
  30. 30.
    Ekins S. A summary of some EU funded Tuberculosis drug discovery collaborations. Drug Discov Today. 2017;22(3):479–80.PubMedGoogle Scholar
  31. 31.
    Anantpadma M, Kouznetsova J, Wang H, Huang R, Kolokoltsov A, Guha R, et al. Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors. Antimicrob Agents Chemother. 2016;60(8):4471–81.Google Scholar
  32. 32.
    Pascoalino BS, Courtemanche G, Cordeiro MT, Gil LH, Freitas-Junior L. Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library. F1000Res. 2016;5:2523.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Kaiser M, Maser P, Tadoori LP, Ioset JR, Brun R. Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning. PLoS One. 2015;10(8):e0135556.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Panic G, Vargas M, Scandale I, Keiser J. Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni. PLoS Negl Trop Dis. 2015;9(7):e0003962.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Edwards MR, Pietzsch C, Vausselin T, Shaw ML, Bukreyev A, Basler CF. High-Throughput Minigenome System for Identifying Small-Molecule Inhibitors of Ebola Virus Replication. ACS Infect Dis. 2015;1(8):380–7.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Planer JD, Hulverson MA, Arif JA, Ranade RM, Don R, Buckner FS. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. PLoS Negl Trop Dis. 2014;8(7):e2977.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016.Google Scholar
  38. 38.
    Cheng H, Lear-Rooney CM, Johansen L, Varhegyi E, Chen ZW, Olinger GG, et al. Inhibition of Ebola and Marburg viral entry by G protein-coupled receptor antagonists. J Virol. 2015.Google Scholar
  39. 39.
    Keenan M, Alexander PW, Chaplin JH, Abbott MJ, Diao H, Wang Z, et al. Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi. Future Med Chem. 2013;5(15):1733–52.Google Scholar
  40. 40.
    Liu J, Dyer D, Wang J, Wang S, Du X, Xu B, et al. 3-oxoacyl-ACP reductase from Schistosoma japonicum: integrated in silico-in vitro strategy for discovering antischistosomal lead compounds. PLoS One. 2013;8(6):e64984.Google Scholar
  41. 41.
    Love MS, Beasley FC, Jumani RS, Wright TM, Chatterjee AK, Huston CD, et al. A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. PLoS Negl Trop Dis, e0005373. 2017;11(2).Google Scholar
  42. 42.
    Johnston KL, Ford L, Umareddy I, Townson S, Specht S, Pfarr K, et al. Repurposing of approved drugs from the human pharmacopoeia to target Wolbachia endosymbionts of onchocerciasis and lymphatic filariasis. Int J Parasitol Drugs Drug Resist. 2014;4(3):278–86.Google Scholar
  43. 43.
    Gunatilleke SS, Calvet CM, Johnston JB, Chen CK, Erenburg G, Gut J, et al. Diverse inhibitor chemotypes targeting Trypanosoma cruzi CYP51. PLoS Negl Trop Dis. 2012;6(7):e1736.Google Scholar
  44. 44.
    Kouznetsova J, Sun W, Martinez-Romero C, Tawa G, Shinn P, Chen CZ, et al. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg Microbes Infect. 2014;3(12):e84.Google Scholar
  45. 45.
    Barrows NJ, Campos RK, Powell ST, Prasanth KR, Schott-Lerner G, Soto-Acosta R, et al. A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. Cell Host Microbe. 2016;20:259–70.Google Scholar
  46. 46.
    Wang Y, Cui R, Li G, Gao Q, Yuan S, Altmeyer R, et al. Teicoplanin inhibits Ebola pseudovirus infection in cell culture. Antivir Res. 2016;125:1–7.Google Scholar
  47. 47.
    Bulman CA, Bidlow CM, Lustigman S, Cho-Ngwa F, Williams D, Rascon AA Jr, et al. Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. PLoS Negl Trop Dis. 2015;9(2):e0003534.Google Scholar
  48. 48.
    Madrid PB, Chopra S, Manger ID, Gilfillan L, Keepers TR, Shurtleff AC, et al. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS One. 2013;8(4):e60579.Google Scholar
  49. 49.
    Zhao Z, Martin C, Fan R, Bourne PE, Xie L. Drug repurposing to target Ebola virus replication and virulence using structural systems pharmacology. BMC Bioinformatics. 2016;17:90.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Johansen LM, DeWald LE, Shoemaker CJ, Hoffstrom BG, Lear-Rooney CM, Stossel A, et al. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. Sci Transl Med. 2015;7(290):290ra289.Google Scholar
  51. 51.
    Johansen LM, Brannan JM, Delos SE, Shoemaker CJ, Stossel A, Lear C, et al. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci Transl Med. 2013;5(190):190ra179.Google Scholar
  52. 52.
    Organization WH. Unprecendented progress against neglected tropical diseases. Available from:
  53. 53.
    Hotez PJ. Ten failings in global neglected tropical diseases control. PLoS Negl Trop Dis. 2017;11(12):e0005896.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32(1):40–51.PubMedGoogle Scholar
  55. 55.
    Van Voorhis WC, Adams JH, Adelfio R, Ahyong V, Akabas MH, Alano P, et al. Open source drug discovery with the malaria box compound collection for neglected diseases and beyond. PLoS Pathog. 2016;12(7):e1005763.Google Scholar
  56. 56.
    Manzano M, Padia J, Padmanabhan R. Small molecule inhibitor discovery for dengue virus protease using high-throughput screening. Methods Mol Biol. 2014;1138:331–44.Google Scholar
  57. 57.
    Uebelhoer LS, Albarino CG, McMullan LK, Chakrabarti AK, Vincent JP, Nichol ST, et al. High-throughput, luciferase-based reverse genetics systems for identifying inhibitors of Marburg and Ebola viruses. Antivir Res. 2014;106:86–94.Google Scholar
  58. 58.
    Alonso-Padilla J, Cotillo I, Presa JL, Cantizani J, Pena I, Bardera AI, et al. Automated high-content assay for compounds selectively toxic to Trypanosoma cruzi in a myoblastic cell line. PLoS Negl Trop Dis. 2015;9(1):e0003493.Google Scholar
  59. 59.
    Calvo-Alvarez E, Stamatakis K, Punzon C, Alvarez-Velilla R, Tejeria A, Escudero-Martinez JM, et al. Infrared fluorescent imaging as a potent tool for in vitro, ex vivo and in vivo models of visceral leishmaniasis. PLoS Negl Trop Dis. 2015;9(3):e0003666.Google Scholar
  60. 60.
    Paape D, Bell AS, Heal WP, Hutton JA, Leatherbarrow RJ, Tate EW, et al. Using a non-image-based medium-throughput assay for screening compounds targeting N-myristoylation in intracellular Leishmania amastigotes. PLoS Negl Trop Dis. 2014;8(12):e3363.Google Scholar
  61. 61.
    Zmurko J, Marques RE, Schols D, Verbeken E, Kaptein SJ, Neyts J. The Viral Polymerase Inhibitor 7-Deaza-2'-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model. PLoS Negl Trop Dis. 2016;10(5):e0004695.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Ochiana SO, Pandarinath V, Wang Z, Kapoor R, Ondrechen MJ, Ruben L, et al. The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposing. Eur J Med Chem. 2013;62:777–84.Google Scholar
  63. 63.
    Patel G, Karver CE, Behera R, Guyett PJ, Sullenberger C, Edwards P, et al. Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis. J Med Chem. 2013;56(10):3820–32.Google Scholar
  64. 64.
    Guyett PJ, Behera R, Ogata Y, Pollastri M, Mensa-Wilmot K. Novel Effects of Lapatinib Revealed in the African Trypanosome by Using Hypothesis-Generating Proteomics and Chemical Biology Strategies. Antimicrob Agents Chemother. 2017;61(2).Google Scholar
  65. 65.
    Mhashilkar AS, Vankayala SL, Liu C, Kearns F, Mehrotra P, Tzertzinis G, et al. Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections. PLoS Negl Trop Dis. 2016;10(6):e0004772.Google Scholar
  66. 66.
    Diaz-Gonzalez R, Kuhlmann FM, Galan-Rodriguez C, Madeira da Silva L, Saldivia M, Karver CE, et al. The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing. PLoS Negl Trop Dis. 2011;5(8):e1297.Google Scholar
  67. 67.
    Hart CJ, Munro T, Andrews KT, Ryan JH, Riches AG, Skinner-Adams TS. A novel in vitro image-based assay identifies new drug leads for giardiasis. Int J Parasitol Drugs Drug Resist. 2017;7(1):83–9.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Lee H, Ren J, Nocadello S, Rice AJ, Ojeda I, Light S, et al. Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus. Antivir Res. 2017;139:49–58.Google Scholar
  69. 69.
    McCarthy SD, Majchrzak-Kita B, Racine T, Kozlowski HN, Baker DP, Hoenen T, et al. A Rapid Screening Assay Identifies Monotherapy with Interferon-ss and Combination Therapies with Nucleoside Analogs as Effective Inhibitors of Ebola Virus. PLoS Negl Trop Dis. 2016;10(1):e0004364.Google Scholar
  70. 70.
    Shahinas D, Debnath A, Benedict C, McKerrow JH, Pillai DR. Heat shock protein 90 inhibitors repurposed against Entamoeba histolytica. Front Microbiol. 2015;6:368.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Sanderson L, Yardley V, Croft SL. Activity of anti-cancer protein kinase inhibitors against Leishmania spp. J Antimicrob Chemother. 2014;69(7):1888–91.PubMedGoogle Scholar
  72. 72.
    Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375(9723):1388–402.PubMedGoogle Scholar
  73. 73.
    Coura JR, Vinas PA. Chagas disease: a new worldwide challenge. Nature. 2010;465(7301):S6–7.PubMedGoogle Scholar
  74. 74.
    Campbell NCR, van Loon JA, Sundaram RS, Ames MM, Hansch C, Weinshilboum R. Human and rat liver phenol sulfotransferase: Structure-activity relationships for phenolic substrates. Mol Pharmacol. 1987;32:813–9.PubMedGoogle Scholar
  75. 75.
    Hotez PJ, Dumonteil E, Woc-Colburn L, Serpa JA, Bezek S, Edwards MS, et al. Chagas disease: "the new HIV/AIDS of the Americas". PLoS Negl Trop Dis. 2012;6(5):e1498.Google Scholar
  76. 76.
    De Rycker M, Thomas J, Riley J, Brough SJ, Miles TJ, Gray DW. Identification of Trypanocidal Activity for Known Clinical Compounds Using a New Trypanosoma cruzi Hit-Discovery Screening Cascade. PLoS Negl Trop Dis. 2016;10(4):e0004584.PubMedPubMedCentralGoogle Scholar
  77. 77.
    De Rycker M, Hallyburton I, Thomas J, Campbell L, Wyllie S, Joshi D, et al. Comparison of a high-throughput high-content intracellular Leishmania donovani assay with an axenic amastigote assay. Antimicrob Agents Chemother. 2013;57(7):2913–22.Google Scholar
  78. 78.
    Riley J, Brand S, Voice M, Caballero I, Calvo D, Read KD. Development of a Fluorescence-based Trypanosoma cruzi CYP51 Inhibition Assay for Effective Compound Triaging in Drug Discovery Programmes for Chagas Disease. PLoS Negl Trop Dis. 2015;9(9):e0004014.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Ekins S, Lage de Siqueira-Neto J, McCall L-I, Sarker M, Yadav M, Ponder EL, et al. Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery. PLoS Negl Trop Dis. 2015;9(6):e0003878.Google Scholar
  80. 80.
    Wiggers HJ, Rocha JR, Fernandes WB, Sesti-Costa R, Carneiro ZA, Cheleski J, et al. Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay. PLoS Negl Trop Dis. 2013;7(8):e2370.Google Scholar
  81. 81.
    Chatelain E. Chagas disease drug discovery: toward a new era. J Biomol Screen. 2015;20(1):22–35.PubMedGoogle Scholar
  82. 82.
    Molina I, Gomez i Prat J, Salvador F, Trevino B, Sulleiro E, Serre N, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas' disease. N Engl J Med. 2014;370(20):1899–908.Google Scholar
  83. 83.
    Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo MJ, Schijman A, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018;18(4):419–30.Google Scholar
  84. 84.
    Sutherland CS, Yukich J, Goeree R, Tediosi F. A literature review of economic evaluations for a neglected tropical disease: human African trypanosomiasis ("sleeping sickness"). PLoS Negl Trop Dis. 2015;9(2):e0003397.PubMedPubMedCentralGoogle Scholar
  85. 85.
    McCall LI, McKerrow JH. Determinants of disease phenotype in trypanosomatid parasites. Trends Parasitol. 2014;30(7):342–9.PubMedGoogle Scholar
  86. 86.
    Mashiyama ST, Koupparis K, Caffrey CR, McKerrow JH, Babbitt PC. A global comparison of the human and T. brucei degradomes gives insights about possible parasite drug targets. PLoS Negl Trop Dis. 2012;6(12):e1942.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Navarro G, Chokpaiboon S, De Muylder G, Bray WM, Nisam SC, McKerrow JH, et al. Hit-to-lead development of the chamigrane endoperoxide merulin A for the treatment of African sleeping sickness. PLoS One. 2012;7(9):e46172.Google Scholar
  88. 88.
    Frevert U, Movila A, Nikolskaia OV, Raper J, Mackey ZB, Abdulla M, et al. Early invasion of brain parenchyma by African trypanosomes. PLoS One. 2012;7(8):e43913.Google Scholar
  89. 89.
    Mackey ZB, Koupparis K, Nishino M, McKerrow JH. High-throughput analysis of an RNAi library identifies novel kinase targets in Trypanosoma brucei. Chem Biol Drug Des. 2011;78(3):454–63.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Watts KR, Ratnam J, Ang KH, Tenney K, Compton JE, McKerrow J, et al. Assessing the trypanocidal potential of natural and semi-synthetic diketopiperazines from two deep water marine-derived fungi. Bioorg Med Chem. 2010;18(7):2566–74.Google Scholar
  91. 91.
    Mallari JP, Shelat AA, Obrien T, Caffrey CR, Kosinski A, Connelly M, et al. Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB. J Med Chem. 2008;51(3):545–52.Google Scholar
  92. 92.
    Vicik R, Hoerr V, Glaser M, Schultheis M, Hansell E, McKerrow JH, et al. Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents. Bioorg Med Chem Lett. 2006;16(10):2753–7.Google Scholar
  93. 93.
    Mackey ZB, O'Brien TC, Greenbaum DC, Blank RB, McKerrow JH. A cathepsin B-like protease is required for host protein degradation in Trypanosoma brucei. J Biol Chem. 2004;279(46):48426–33.PubMedGoogle Scholar
  94. 94.
    Greenbaum DC, Mackey Z, Hansell E, Doyle P, Gut J, Caffrey CR, et al. Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi. J Med Chem. 2004;47(12):3212–9.Google Scholar
  95. 95.
    Caffrey CR, Schanz M, Nkemngu NJ, Brush M, Hansell E, Cohen FE, et al. Screening of acyl hydrazide proteinase inhibitors for antiparasitic activity against Trypanosoma brucei. Int J Antimicrob Agents. 2002;19(3):227–31.Google Scholar
  96. 96.
    Caffrey CR, Hansell E, Lucas KD, Brinen LS, Alvarez Hernandez A, Cheng J, et al. Active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of Trypanosoma brucei rhodesiense. Mol Biochem Parasitol. 2001;118(1):61–73.Google Scholar
  97. 97.
    Troeberg L, Chen X, Flaherty TM, Morty RE, Cheng M, Hua H, et al. Chalcone, acyl hydrazide, and related amides kill cultured Trypanosoma brucei brucei. Mol Med. 2000;6(8):660–9.Google Scholar
  98. 98.
    Troeberg L, Morty RE, Pike RN, Lonsdale-Eccles JD, Palmer JT, McKerrow JH, et al. Cysteine proteinase inhibitors kill cultured bloodstream forms of Trypanosoma brucei brucei. Exp Parasitol. 1999;91(4):349–55.Google Scholar
  99. 99.
    Blaazer AR, Orrling KM, Shanmugham A, Jansen C, Maes L, Edink E, et al. Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits. J Biomol Screen. 2015;20(1):131–40.Google Scholar
  100. 100.
    Bland ND, Wang C, Tallman C, Gustafson AE, Wang Z, Ashton TD, et al. Pharmacological validation of Trypanosoma brucei phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness. J Med Chem. 2011;54(23):8188–94.Google Scholar
  101. 101.
    Njogu PM, Guantai EM, Pavadai E, Chibale K. Computer-Aided Drug Discovery Approaches against the Tropical Infectious Diseases Malaria, Tuberculosis, Trypanosomiasis, and Leishmaniasis. ACS Infect Disease. 2016;2:8–31.Google Scholar
  102. 102.
    McCall LI, El Aroussi A, Choi JY, Vieira DF, De Muylder G, Johnston JB, et al. Targeting Ergosterol Biosynthesis in Leishmania donovani: Essentiality of Sterol 14alpha-demethylase. PLoS Negl Trop Dis. 2015;9(3):e0003588.Google Scholar
  103. 103.
    Sanchez LM, Knudsen GM, Helbig C, De Muylder G, Mascuch SM, Mackey ZB, et al. Examination of the mode of action of the almiramide family of natural products against the kinetoplastid parasite Trypanosoma brucei. J Nat Prod. 2013;76(4):630–41.Google Scholar
  104. 104.
    Ben Khalaf N, De Muylder G, Louzir H, McKerrow J, Chenik M. Leishmania major protein disulfide isomerase as a drug target: enzymatic and functional characterization. Parasitol Res. 2012;110(5):1911–7.PubMedGoogle Scholar
  105. 105.
    De Muylder G, Ang KK, Chen S, Arkin MR, Engel JC, McKerrow JH. A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. PLoS Negl Trop Dis. 2011;5(7):e1253.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Swenerton RK, Zhang S, Sajid M, Medzihradszky KF, Craik CS, Kelly BL, et al. The oligopeptidase B of Leishmania regulates parasite enolase and immune evasion. J Biol Chem. 2011;286(1):429–40.Google Scholar
  107. 107.
    Chen CK, Leung SS, Guilbert C, Jacobson MP, McKerrow JH, Podust LM. Structural characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei bound to the antifungal drugs posaconazole and fluconazole. PLoS Negl Trop Dis. 2010;4(4):e651.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Zhang S, Kim CC, Batra S, McKerrow JH, Loke P. Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines. PLoS Negl Trop Dis. 2010;4(3):e648.PubMedPubMedCentralGoogle Scholar
  109. 109.
    McKerrow JH, Rosenthal PJ, Swenerton R, Doyle P. Development of protease inhibitors for protozoan infections. Curr Opin Infect Dis. 2008;21(6):668–72.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Fricker SP, Mosi RM, Cameron BR, Baird I, Zhu Y, Anastassov V, et al. Metal compounds for the treatment of parasitic diseases. J Inorg Biochem. 2008;102(10):1839–45.Google Scholar
  111. 111.
    McKerrow JH, Caffrey C, Kelly B, Loke P, Sajid M. Proteases in parasitic diseases. Annu Rev Pathol. 2006;1:497–536.PubMedGoogle Scholar
  112. 112.
    Mahmoudzadeh-Niknam H, McKerrow JH. Leishmania tropica: cysteine proteases are essential for growth and pathogenicity. Exp Parasitol. 2004;106(3-4):158–63.PubMedGoogle Scholar
  113. 113.
    Selzer PM, Pingel S, Hsieh I, Ugele B, Chan VJ, Engel JC, et al. Cysteine protease inhibitors as chemotherapy: lessons from a parasite target. Proc Natl Acad Sci U S A. 1999;96(20):11015–22.Google Scholar
  114. 114.
    Scheidt KA, Roush WR, McKerrow JH, Selzer PM, Hansell E, Rosenthal PJ. Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem. 1998;6(12):2477–94.PubMedGoogle Scholar
  115. 115.
    McKerrow JH, Sun E, Rosenthal PJ, Bouvier J. The proteases and pathogenicity of parasitic protozoa. Annu Rev Microbiol. 1993;47:821–53.PubMedGoogle Scholar
  116. 116.
    Nuhs A, De Rycker M, Manthri S, Comer E, Scherer CA, Schreiber SL, et al. Development and Validation of a Novel Leishmania donovani Screening Cascade for High-Throughput Screening Using a Novel Axenic Assay with High Predictivity of Leishmanicidal Intracellular Activity. PLoS Negl Trop Dis. 2015;9(9):e0004094.Google Scholar
  117. 117.
    Pena I, Pilar Manzano M, Cantizani J, Kessler A, Alonso-Padilla J, Bardera AI, et al. New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: an open resource. Sci Rep. 2015;5:8771.Google Scholar
  118. 118.
    Kaiser M, Maes L, Tadoori LP, Spangenberg T, Ioset JR. Repurposing of the Open Access Malaria Box for Kinetoplastid Diseases Identifies Novel Active Scaffolds against Trypanosomatids. J Biomol Screen. 2015;20(5):634–45.PubMedGoogle Scholar
  119. 119.
    Hotez PJ. Preface. In: Caffrey CR, editor. Parasitic Helminths Targets, Screens, Drugs and Vaccines. Weinheim: Wiley-Blackwell; 2012. p. XIGoogle Scholar
  120. 120.
    Ekpo UF, Oluwole AS, Abe EM, Etta HE, Olamiju F, Mafiana CF. Schistosomiasis in infants and pre-school-aged children in sub-Saharan Africa: implication for control. Parasitology. 2012;139(7):835–41.PubMedGoogle Scholar
  121. 121.
    Colley DG, Bustinduy AL, Secor WE, King CH. Human schistosomiasis. Lancet. 2014;383(9936):2253–64.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Naing C, Whittaker MA, Nyunt-Wai V, Reid SA, Wong SF, Mak JW, et al. Malaria and soil-transmitted intestinal helminth co-infection and its effect on anemia: a meta-analysis. Trans R Soc Trop Med Hyg. 2013;107(11):672–83.Google Scholar
  123. 123.
    Kobylinski KC, Alout H, Foy BD, Clements A, Adisakwattana P, Swierczewski BE, et al. Rationale for the Coadministration of Albendazole and Ivermectin to Humans for Malaria Parasite Transmission Control. Am J Trop Med Hyg. 2014.Google Scholar
  124. 124.
    Caffrey CR. Parasitic Helminths: Targets, Screens, Drugs and Vaccines. Wiley-Blackwell: Weinheim; 2012.Google Scholar
  125. 125.
    Feldmeier H, Krantz I, Poggensee G. Female genital schistosomiasis as a risk-factor for the transmission of HIV. Int J STD AIDS. 1994;5(5):368–72.PubMedGoogle Scholar
  126. 126.
    Kjetland EF, Ndhlovu PD, Gomo E, Mduluza T, Midzi N, Gwanzura L, et al. Association between genital schistosomiasis and HIV in rural Zimbabwean women. AIDS. 2006;20(4):593–600.Google Scholar
  127. 127.
    Christinet V, Lazdins-Helds JK, Stothard JR, Reinhard-Rupp J. Female genital schistosomiasis (FGS): from case reports to a call for concerted action against this neglected gynaecological disease. Int J Parasitol. 2016;46(7):395–404.PubMedGoogle Scholar
  128. 128.
    Keiser J, Utzinger J. The drugs we have and the drugs we need against major helminth infections. Adv Parasitol. 2010;73:197–230.PubMedGoogle Scholar
  129. 129.
    Gabrielli AF, Montresor A, Chitsulo L, Engels D, Savioli L. Preventive chemotherapy in human helminthiasis: theoretical and operational aspects. Trans R Soc Trop Med Hyg. 2011;105(12):683–93.PubMedPubMedCentralGoogle Scholar
  130. 130.
    van den Enden E. Pharmacotherapy of helminth infection. Expert Opin Pharmacother. 2009;10(3):435–51.PubMedGoogle Scholar
  131. 131.
    Caffrey CR, editor. Parasitic Helminths: Targets, Screens, Drugs and Vaccines. Weinheim: Wiley-Blackwell; 2012.Google Scholar
  132. 132.
    Caffrey CR. Schistosomiasis and its treatment. Future Med Chem. 2015;7(6):675–6.PubMedGoogle Scholar
  133. 133.
    Panic G, Flores D, Ingram-Sieber K, Keiser J. Fluorescence/luminescence-based markers for the assessment of Schistosoma mansoni schistosomula drug assays. Parasit Vectors. 2015;8:624.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Abdulla MH, Ruelas DS, Wolff B, Snedecor J, Lim KC, Xu F, et al. Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. PLoS Negl Trop Dis. 2009;3(7):e478.Google Scholar
  135. 135.
    Singh R, Pittas, M., Heskia, I., Xu, F., McKerrow, J. H., Caffrey, C. R. Automated image-based phenotypic screening for high-throughput drug discovery. In.IEEE Symposium on Computer-Based Medical Systems Albuquerque, NM; 2009. p. 1-8.Google Scholar
  136. 136.
    Lee H, Moody-Davis A, Saha U, Suzuki BM, Asarnow D, Chen S, et al. Quantification and clustering of phenotypic screening data using time-series analysis for chemotherapy of schistosomiasis. BMC Genomics. 2012;13(Suppl 1):S4.Google Scholar
  137. 137.
    Asarnow D, Rojo-Arreola L, Suzuki BM, Caffrey CR, Singh R. The QDREC web server: determining dose-response characteristics of complex macroparasites in phenotypic drug screens. Bioinformatics. 2014.Google Scholar
  138. 138.
    Paveley RA, Mansour NR, Hallyburton I, Bleicher LS, Benn AE, Mikic I, et al. Whole organism high-content screening by label-free, image-based Bayesian classification for parasitic diseases. PLoS Negl Trop Dis. 2012;6(7):e1762.Google Scholar
  139. 139.
    Caffrey CR. Chemotherapy of schistosomiasis: present and future. Curr Opin Chem Biol. 2007;11(4):433–9.PubMedGoogle Scholar
  140. 140.
    Caffrey CR, Secor WE. Schistosomiasis: from drug deployment to drug development. Curr Opin Infect Dis. 2011;24(5):410–7.PubMedGoogle Scholar
  141. 141.
    Nwaka S, Ramirez B, Brun R, Maes L, Douglas F, Ridley R. Advancing drug innovation for neglected diseases-criteria for lead progression. PLoS Negl Trop Dis. 2009;3(8):e440.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Andrews P, Thomas H, Pohlke R, Seubert J. Praziquantel. Med Res Rev. 1983;3(2):147–200.PubMedGoogle Scholar
  143. 143.
    Sabah AA, Fletcher C, Webbe G, Doenhoff MJ. Schistosoma mansoni: chemotherapy of infections of different ages. Exp Parasitol. 1986;61(3):294–303.PubMedGoogle Scholar
  144. 144.
    Xiao SH, Yue WJ, Yang YQ, You JQ. Susceptibility of Schistosoma japonicum to different developmental stages to praziquantel. Chin Med J. 1987;100(9):759–68.PubMedGoogle Scholar
  145. 145.
    Ingram-Sieber K, Cowan N, Panic G, Vargas M, Mansour NR, Bickle QD, et al. Orally active antischistosomal early leads identified from the open access malaria box. PLoS Negl Trop Dis. 2014;8(1):e2610.Google Scholar
  146. 146.
    Fonseca NC, da Cruz LF, Villela FD, Pereira GA, de Siqueira-Neto JL, Kellar D, et al. Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases: rhodesain, cruzain and Schistosoma mansoni cathepsin B1. Antimicrob Agents Chemother. 2015.Google Scholar
  147. 147.
    Rojo-Arreola L, Long T, Asarnow D, Suzuki BM, Singh R, Caffrey CR. Chemical and genetic validation of the statin drug target to treat the helminth disease, schistosomiasis. PLoS One. 2014;9(1):e87594.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Kannan S, Melesina J, Hauser AT, Chakrabarti A, Heimburg T, Schmidtkunz K, et al. Discovery of inhibitors of Schistosoma mansoni HDAC8 by combining homology modeling, virtual screening, and in vitro validation. J Chem Inf Model. 2014;54(10):3005–19.Google Scholar
  149. 149.
    Kuntz AN, Davioud-Charvet E, Sayed AA, Califf LL, Dessolin J, Arner ES, et al. Thioredoxin glutathione reductase from Schistosoma mansoni: an essential parasite enzyme and a key drug target. PLoS Med. 2007;4(6):e206.Google Scholar
  150. 150.
    Neves BJ, Dantas RF, Senger MR, Melo-Filho CC, Valente WC, de Almeida AC, et al. Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening. J Med Chem. 2016;59(15):7075–88.Google Scholar
  151. 151.
    Long T, Rojo-Arreola L, Shi D, El-Sakkary N, Jarnagin K, Rock F, et al. Phenotypic, chemical and functional characterization of cyclic nucleotide phosphodiesterase 4 (PDE4) as a potential anthelmintic drug target. PLoS Negl Trop Dis. 2017;11(7):e0005680.Google Scholar
  152. 152.
    Neves BJ, Braga RC, Bezerra JC, Cravo PV, Andrade CH. In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni. PLoS Negl Trop Dis. 2015;9(1):e3435.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Neves BJ, Dantas RF, Senger MB, Valente WCG, Rezende-Neto JD, Chaves WT, et al. AC. The antidepressant drug paroxetine as a new lead candidate in schistosome drug discovery. ChemMedChem. 2016;7:1176–82.Google Scholar
  154. 154.
    Burns AR, Luciani GM, Musso G, Bagg R, Yeo M, Zhang Y, et al. Caenorhabditis elegans is a useful model for anthelmintic discovery. Nat Commun. 2015;6:7485.Google Scholar
  155. 155.
    Mathew MD, Mathew ND, Miller A, Simpson M, Au V, Garland S, et al. Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity. PLoS Negl Trop Dis. 2016;10(10):e0005058.Google Scholar
  156. 156.
    Crowther GJ, Booker ML, He M, Li T, Raverdy S, Novelli JF, et al. Cofactor-independent phosphoglycerate mutase from nematodes has limited druggability, as revealed by two high-throughput screens. PLoS Negl Trop Dis. 2014;8(1):e2628.Google Scholar
  157. 157.
    Bilsland E, Bean DM, Devaney E, Oliver SG. Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi. PLoS Negl Trop Dis. 2016;10(1):e0004401.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Stadelmann B, Rufener R, Aeschbacher D, Spiliotis M, Gottstein B, Hemphill A. Screening of the Open Source Malaria Box Reveals an Early Lead Compound for the Treatment of Alveolar Echinococcosis. PLoS Negl Trop Dis. 2016;10(3):e0004535.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Pothineni VR, Wagh D, Babar MM, Inayathullah M, Solow-Cordero D, Kim KM, et al. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening. Drug Des Devel Ther. 2016;10:1307–22.Google Scholar
  160. 160.
    Boyom FF, Fokou PV, Tchokouaha LR, Spangenberg T, Mfopa AN, Kouipou RM, et al. Repurposing the open access malaria box to discover potent inhibitors of Toxoplasma gondii and Entamoeba histolytica. Antimicrob Agents Chemother. 2014;58(10):5848–54.Google Scholar
  161. 161.
    Witola WH, Mui E, Hargrave A, Liu S, Hypolite M, Montpetit A, et al. NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells. Infect Immun. 2011;79(2):756–66.Google Scholar
  162. 162.
    Cruz DJ, Koishi AC, Taniguchi JB, Li X, Milan Bonotto R, No JH, et al. High content screening of a kinase-focused library reveals compounds broadly-active against dengue viruses. PLoS Negl Trop Dis. 2013;7(2):e2073.Google Scholar
  163. 163.
    WHO. Dengue and severe dengue. Available from:
  164. 164.
    Lim SP, Wang QY, Noble CG, Chen YL, Dong H, Zou B, et al. Ten years of dengue drug discovery: progress and prospects. Antivir Res. 2013;100(2):500–19.Google Scholar
  165. 165.
    Yang CC, Hu HS, Wu RH, Wu SH, Lee SJ, Jiaang WT, et al. A novel dengue virus inhibitor, BP13944, discovered by high-throughput screening with dengue virus replicon cells selects for resistance in the viral NS2B/NS3 protease. Antimicrob Agents Chemother. 2014;58(1):110–9.Google Scholar
  166. 166.
    Cheung YY, Chen KC, Chen H, Seng EK, Chu JJ. Antiviral activity of lanatoside C against dengue virus infection. Antivir Res. 2014;111:93–9.PubMedGoogle Scholar
  167. 167.
    Basavannacharya C, Vasudevan SG. Suramin inhibits helicase activity of NS3 protein of dengue virus in a fluorescence-based high throughput assay format. Biochem Biophys Res Commun. 2014;453(3):539–44.PubMedGoogle Scholar
  168. 168.
    Chu JJ, Yang PL. c-Src protein kinase inhibitors block assembly and maturation of dengue virus. Proc Natl Acad Sci U S A. 2007;104(9):3520–5.PubMedPubMedCentralGoogle Scholar
  169. 169.
    Faye O, Freire CC, Iamarino A, Faye O, de Oliveira JV, Diallo M, et al. Molecular evolution of Zika virus during its emergence in the 20(th) century. PLoS Negl Trop Dis. 2014;8(1):e2636.Google Scholar
  170. 170.
    Coffee M. Understanding the Zika Outreak and Why It's Rapidly Spreading. Available from:
  171. 171.
    Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastere S, Valour F, et al. Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013. Euro Surveill. 2014;19(9).Google Scholar
  172. 172.
    Smith DW, Mackenzie J. Zika virus and Guillain-Barre syndrome: another viral cause to add to the list. Lancet. 2016;387(10027):1486–8.PubMedGoogle Scholar
  173. 173.
    Faria NR, Azevedo Rdo S, Kraemer MU, Souza R, Cunha MS, Hill SC, et al. Zika virus in the Americas: Early epidemiological and genetic findings. Science. 2016;352(6283):345–9.Google Scholar
  174. 174.
    Anon. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. Available from:
  175. 175.
    Ekins S, Mietchen D, Coffee M, Stratton TP, Freundlich JS, Freitas-Junior L, et al. Open drug discovery for the Zika virus. F1000Res. 2016;5:150.Google Scholar
  176. 176.
    Shan C, Xie X, Barrett AD, Garcia-Blanco MA, Tesh RB, Vasconcelos PF, et al. Zika Virus: Diagnosis, Therapeutics, and Vaccine. ACS Infect Dis. 2016;2:170–2.Google Scholar
  177. 177.
    Malone RW, Homan J, Callahan MV, Glasspool-Malone J, Damodaran L, Schneider Ade B, et al. Zika Virus: Medical Countermeasure Development Challenges. PLoS Negl Trop Dis. 2016;10(3):e0004530.Google Scholar
  178. 178.
    Mottin M, Borba JVVB, Melo-Filho CC, Neves BJ, Muratov E., Torres PHM, Braga RC, Perryman A, Ekins S, Andrade CH. Computational Drug Discovery for the Zika Virus. Brazilian Journal of Pharmaceutical Sciences. 2018;In Press.Google Scholar
  179. 179.
    Ekins S, Perryman AL, Horta AC. OpenZika: An IBM World Community Grid Project to Accelerate Zika Virus Drug Discovery. PLoS Negl Trop Dis. 2016;10(10):e0005023.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Mottin M, Borba J, Braga RC, Torres PHM, Martini MC, Proenca-Modena JL, Judice CC, Costa FTM, Ekins S, Perryman AL, Horta Andrade C. The A-Z of Zika drug discovery. Drug Discov Today. 2018.Google Scholar
  181. 181.
    Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016;22(10):1101–7.Google Scholar
  182. 182.
    Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci U S A. 2016;113(50):14408–13.Google Scholar
  183. 183.
    Ekins S, Southan C, Coffee M. Finding small molecules for the 'next Ebola'. F1000Res. 2015;4:58.PubMedPubMedCentralGoogle Scholar
  184. 184.
    Johansen LM, Brannan JM, Delos SE, Shoemaker CJ, Stossel A, Lear C, et al. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci Transl Med. 2013;5(190)):190ra179–9.Google Scholar
  185. 185.
    Towner JS, Paragas J, Dover JE, Gupta M, Goldsmith CS, Huggins JW, et al. Generation of eGFP expressing recombinant Zaire ebolavirus for analysis of early pathogenesis events and high-throughput antiviral drug screening. Virology. 2005;332(1):20–7.Google Scholar
  186. 186.
    Cheng H, Lear-Rooney CM, Johansen L, Varhegyi E, Chen ZW, Olinger GG, et al. Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists. J Virol. 2015;89(19):9932–8.Google Scholar
  187. 187.
    Ekins S, Freundlich JS, Clark AM, Anantpadma M, Davey RA, Madrid P. Machine learning models identify molecules active against the Ebola virus in vitro. F1000Res. 2016;4:1091.Google Scholar
  188. 188.
    Ekins S, Lingerfelt MA, Comer JE, Freiberg AN, Mirsalis JC, O’Loughlin K, Harutyunyan A, McFarlane C, Green CE, Madrid PB. Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection. Antimicrob Agents Chemother. 2017;In Press.Google Scholar
  189. 189.
    Mirza MU, Ikram N. Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40. Int J Mol Sci. 2016;17(11).Google Scholar
  190. 190.
    Chopra G, Kaushik S, Elkin PL, Samudrala R. Combating Ebola with Repurposed Therapeutics Using the CANDO Platform. Molecules. 2016;21(12).Google Scholar
  191. 191.
    Mudhasani R, Kota KP, Retterer C, Tran JP, Whitehouse CA, Bavari S. High content image-based screening of a protease inhibitor library reveals compounds broadly active against Rift Valley fever virus and other highly pathogenic RNA viruses. PLoS Negl Trop Dis. 2014;8(8):e3095.PubMedPubMedCentralGoogle Scholar
  192. 192.
    Cruz DJ, Bonotto RM, Gomes RG, da Silva CT, Taniguchi JB, No JH, et al. Identification of novel compounds inhibiting chikungunya virus-induced cell death by high throughput screening of a kinase inhibitor library. PLoS Negl Trop Dis. 2013;7(10):e2471.Google Scholar
  193. 193.
    Karlas A, Berre S, Couderc T, Varjak M, Braun P, Meyer M, et al. A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs. Nat Commun. 2016;7:11320.Google Scholar
  194. 194.
    Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014;58(8):4885–93.Google Scholar
  195. 195.
    Oprea TI, Allu TK, Fara DC, Rad RF, Ostopovici L, Bologa CG. Lead-like, drug-like or "Pub-like": how different are they? J Comput Aided Mol Des. 2007;21(1-3):113–9.PubMedPubMedCentralGoogle Scholar
  196. 196.
    Lane T, Russo DP, Zorn KM, Clark AM, Korotcov A, Tkachenko V, Reynolds RC, Perryman AL, Freundlich JS, Ekins S. Comparing and Validating Machine Learning Models for Mycobacterium tuberculosis Drug Discovery. Mol Pharm. 2018.Google Scholar
  197. 197.
    Russo DP, Zorn KM, Clark AM, Zhu H, Ekins S. Comparing Multiple Machine Learning Algorithms and Metrics for Estrogen Receptor Binding Prediction. Mol Pharmaceutics. 2018.Google Scholar
  198. 198.
    Sandoval PJ, Zorn KM, Clark AM, Ekins S, Wright SH. Assessment of Substrate Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates. Mol Pharmacol. 2018.Google Scholar
  199. 199.
    Ekins S, Freundlich J, Clark A, Anantpadma M, Davey R, Madrid P. Machine learning models identify molecules active against Ebola virus in vitro. F1000Res. 2015;4:1091.PubMedGoogle Scholar
  200. 200.
    Guiguemde WA, Shelat AA, Garcia-Bustos JF, Diagana TT, Gamo FJ, Guy RK. Global phenotypic screening for antimalarials. Chem Biol. 2012;19(1):116–29.PubMedPubMedCentralGoogle Scholar
  201. 201.
    Tarral A, Blesson S, Mordt OV, Torreele E, Sassella D, Bray MA, et al. Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: first-in-human studies. Clin Pharmacokinet. 2014;53(6):565–80.Google Scholar
  202. 202.
    Raether W, Seidenath H. The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica. Ann Trop Med Parasitol. 1983;77(1):13–26.PubMedGoogle Scholar
  203. 203.
    Bahia MT, de Andrade IM, Martins TA, do Nascimento AF, Diniz Lde F, Caldas IS, et al. Fexinidazole: a potential new drug candidate for Chagas disease. PLoS Negl Trop Dis. 2012;6(11):e1870.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.KAL Research Initiatives LLCHoustonUSA
  2. 2.MD Anderson Cancer CenterUniversity of TexasHoustonUSA
  3. 3.Collaborations Pharmaceuticals Inc.RaleighUSA
  4. 4.University of Texas at AustinAustinUSA
  5. 5.LabMol - Laboratory for Molecular Modeling and Drug Design Faculdade de FarmaciaUniversidade Federal de Goias – UFGGoiâniaBrazil
  6. 6.Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of California San DiegoSan DiegoUSA

Personalised recommendations