1. Academy of Chinese Medicine Henan University of Chinese Medicine, Zhengzhou 450046, China; 2. College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, China
Abstract：Cryptosporidium is an important opportunistic pathogenic zoonotic protozoan, as well as the Cryptosporidium is also the second largest diarrhea-causing pathogen in children in developing countries. The cryptosporidiosis caused nearly 8.4 million disability-adjusted life years each year in world. Cryptosporidium was first discovered and named by Tyzzer in 1907. So far, 36 species and more than 60 genotypes have been identified. More than 90% of human Cryptosporidium infections are caused by C. hominis and C. parvum. Cryptosporidium has been identified by the World Health Organization (WHO) as one of the six major causes of human diarrhea. Now, nitazoxanide is the only drug used and approved by the US FDA to treat the human cryptosporidiosis, however it is ineffective for AIDS patients with Cryptosporidium infection. Due to the urgent need of anti-cryptosporidium drugs in clinic, more than two hundred drugs or compounds have been studied for the treatment of cryptosporidiosis in the recent years. However, up to now, there is still no suitable drugs screened for anti-cryptosporidium. In this paper, we will review the kinds and action mechanisms of anti-cryptosporidium drugs in recent years of domestic and overseas studies. We are hoping to provide help for clinical treatment of cryptosporidiosis in future.
[1] Ryan U, Fayer R, Xiao L.Cryptosporidium species in humans and animals: current understanding and research needs[J]. Parasitology, 2014, 141(13): 1667-1685. DOI: 10.1017/S0031182014001085 [2] Wang RJ, Li JQ, Chen YC, et al.Widespread occurrence of Cryptosporidium infections in patients with HIV/AIDS: Epidemiology, clinical feature, diagnosis, and therapy[J]. Acta Trop, 2018, 187: 257-263. DOI: 10.1016/j.actatropica.2018.08.018 [3] Feng Y, Ryan UM, Xiao L.Genetic diversity and population structure of Cryptosporidium[J]. Trends Parasitol, 2018, 34(11): 997-1011. DOI: 10.1016/j.pt.2018.07.009 [4] Ryan U, Hijjawi N, Xiao L.Foodborne cryptosporidiosis[J]. Int J Parasitol, 2018, 48(1):1-12. DOI: 10.1016/j.ijpara.2017.09.004. [5] Kotloff KL, Nataro JP, Blackwelder WC, et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study[J]. Lancet, 2013, 382(9888): 209-222. DOI: 10.1016/S0140-6736(13)60844-2 [6] Cacciò SM, Chalmers RM.Human cryptosporidiosis in Europe[J]. Clin Microbiol Infect, 2016, 22(6): 471-480. DOI: 10.1016/j.cmi.2016.04.021 [7] 沈一平, 管晓虹, 冯振卿. 广谱抗肠道寄生虫药硝唑尼特(nitazoxanide)研究进展[J]. 国际医学寄生虫病杂志, 2006, 33(4): 221-224. [8] Amadi B, Mwiya M, Musuku J, et al.Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial[J]. Lancet, 2002, 360(9343): 1375-1380. DOI: 10.1016/S0140-6736(02)11401-2 [9] Amadi B, Mwiya M, Sianongo S, et al.High dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in HIV positive Zambian children: a randomised controlled trial[J]. BMC Infect Dis, 2009, 9: 195. DOI: 10.1186/1471-2334-9-195 [10] Cabada MM, White AC Jr.Treatment of cryptosporidiosis: do we know what we think we know?[J]. Curr Opin Infect Dis, 2010,23(5): 494-499. DOI: 10.1097/QCO.0b013e32833de052 [11] Manjunatha UH, Chao AT, Leong FJ, et al.Cryptosporidiosis Drug Discovery: Opportunities and Challenges[J]. ACS Infect Dis, 2016, 2(8): 530-537. DOI: 10.1021/acsinfecdis.6b00094 [12] Bhadauria D, Goel A, Kaul A, et al.Cryptosporidium infection after renal transplantation in an endemic area[J]. Transpl Infect Dis, 2015, 17(1): 48-55. DOI: 10.1111/tid.12336 [13] Chavez MA, White AC Jr.Novel treatment strategies and drugs in development for cryptosporidiosis[J]. Expert Rev Anti Infect Ther, 2018, 16(8): 655-661. DOI: 10.1080/14787210.2018.1500457 [14] White AC Jr., Chappell CL, Hayat CS, et al.Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial[J]. J Infect Dis, 1994, 170(2): 419-424. DOI: 10.1093/infdis/170.2.419 [15] Hussien SM, Abdella OH, Abu-Hashim AH, et al.Comparative study between the effect of nitazoxanide and paromomycine in treatment of cryptosporidiosis in hospitalized children[J]. J Egypt Soc Parasitol, 2013, 43(2): 463-470. [16] Allam AF, Shehab AY.Efficacy of azithromycin, praziquantel and mirazid in treatment of cryptosporidiosis in school children[J]. J Egypt Soc Parasitol, 2002, 32(3): 969-978. [17] Smith NH, Cron S, Waldez LM, et al.Combination drug therapy for Cryptosporidiosis in AIDS[J]. J Infect Dis, 1998, 178(3): 900-903 DOI: 10.1086/515352 [18] Lanternier F, Amazzough K, Favennec L, et al.Cryptosporidium spp. infection in solid organ transplantation: the nationwide “TRANSCRYPTO” Study[J]. Transplantation, 2017, 101(4): 826-830. DOI: 10.1097/TP.0000000000001503 [19] 杨娜, 李凤, 程卯生. 隐孢子虫病的化学治疗研究进展[J]. 沈阳药科大学学报, 2011, 8: 649-657. [20] 王东,张媛媛.大蒜素和阿奇霉素治疗隐孢子虫感染小鼠的效果观察[J]. 中国寄生虫学与寄生虫病杂志, 2013, 31(6): 477-479. [21] 杨硕平,戈建军,沈京培.大蒜素治疗婴幼儿隐孢子虫感染性腹泻172例临床报告[J]. 中国医药学报, 1994, 3: 49. [22] 沈玲君,戈建军,沈京培.大蒜素治疗婴幼儿隐孢子虫病(附202例报告)[J]. 江苏医药, 1997, 23(8): 571. [23] 温泉. 大蒜素治疗幼儿隐孢子虫病的研究[J].中国医药指南, 2010, 8(15): 122-123. [24] Huang MZ, Li J, Guan L, et al.Therapeutic effects of acetylspiramycin and garlicin on cryptosporidiosis among drug users[J]. Int J Parasitol Drugs Drug Resist, 2015, 5(3): 185-190. DOI: 10.1016/j.ijpddr.2015.09.002 [25] 张珍,郭立东,耿丽,等.大蒜素对免疫抑制合并隐孢子虫感染小鼠的治疗与免疫功能的作用观察[J]. 时珍国医国药, 2009, 20(3): 718-719. [26] Linder MR, Heckeroth AR, Najdrowski m, et al.(2R,3S)-(+)- and (2S,3R)-(-)-Halofuginone lactate: Synthesis, absolute configuration, and activity against Cryptosporidium parvum[J]. Bioorg Med Chem Lett, 2007, 17(15): 4140-4143. DOI: 10.1016/j.bmcl.2007.05.053 [27] Asadpour M, Namazi F, Razavi SM, et al.Curcumin: A promising treatment for Cryptosporidium parvum infection in immunosuppressed BALB/c mice[J]. Exp Parasitol, 2018, 195: 59-65. DOI: 10.1016/j.exppara.2018.10.008 [28] Stancu C, Sima A.Statins: mechanism of action and effects[J]. J Cell Mol Med, 2001, 5(4): 378-387. DOI: 10.1111/j.1582-4934.2001.tb00172.x [29] Bessoff K, Sateriale A, Lee KK, et al.Drug repurposing screen reveals FDA-approved inhibitors of human HMG-CoA reductase and isoprenoid synthesis that block Cryptosporidium parvum growth[J]. Antimicrob Agents Chemother, 2013, 57(4): 1804-1814. DOI: 10.1128/AAC.02460-12 [30] Madbouly Taha N, Salah AYHA, El-Sayed SH, et al.Atorvastatin repurposing for the treatment of cryptosporidiosis in experimentally immunosuppressed mice[J]. Exp Parasitol, 2017, 181: 57-69. DOI: 10.1016/j.exppara.2017.07.010 [31] Love MS, Beasley FC, Jumani RS, et al.A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis[J]. PLoS Negl Trop Dis, 2017, 11(2): e0005373. DOI: 10.1371/journal.pntd.0005373 [32] Zhang Y, Feng J, McManus SA, et al. Design and solidification of fast-releasing clofazimine nanoparticles for treatment of cryptosporidiosis[J]. Mol Pharm, 2017, 14(10): 3480-3488. DOI: 10.1021/acs.molpharmaceut.7b00521 [33] Nachipo P, Hermann D, Quinnan G, et al.Evaluating the safety, tolerability, pharmacokinetics and efficacy of clofazimine in cryptosporidiosis (CRYPTOFAZ): study protocol for a randomized controlled trial[J]. Trials, 2018, 19(1): 456. DOI: 10.1186/s13063-018-2846-6 [34] Bondioli L, Ludovisi A, Tosi G, et al.The loading of labelled antibody-engineered nanoparticles with Indinavir increases its in vitro efficacy against Cryptosporidium parvum[J]. Parasitology, 2011,138(11):1384-1391. DOI: 10.1017/S003118-2011001119 [35] Downey AS, Chong CR, Graczyk TK, et al.Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model[J]. Antimicrob Agents Chemother, 2008, 52(9): 3106-3112. DOI: 10.1128/AAC.00207-08 [36] Murphy RC, Ojo KK, Larson ET, et al.Discovery of potent and selective inhibitors of calcium-dependent protein kinase 1 (CDPK1) from C. parvum and T. gondii[J]. ACS Med Chem Lett, 2010, 1(7): 331-335. DOI: 10.1021/ml100096t [37] Castellanos-Gonzalez A, Sparks H, Nava S, et al.A novel calciumdependent kinase inhibitor, bumped kinase inhibitor-1517, cures cryptosporidiosis in immunosuppressed mice[J]. J Infect Dis, 2016, 214(12): 1850-1855. DOI: 10.1093/infdis/jiw481 [38] Schaefer DA, Betzer DP, Smith KD, et al.Novel bumped kinase inhibitors are safe and effective therapeutics in the calf clinical model for cryptosporidiosis[J]. J Infect Dis, 2016, 214(12): 1856-1864. DOI: 10.1093/infdis/jiw488 [39] Hulverson MA, Vinayak S, Choi R, et al.Bumped-kinase inhibitors for cryptosporidiosis therapy[J]. J Infect Dis, 2017, 215(8): 1275-1284. DOI: 10.1093/infdis/jix120 [40] Lendner M, Bottcher D, Delling C, et al.A novel CDPK1 inhibitor-a potential treatment for cryptosporidiosis in calves?[J]. Parasitol Res, 2015, 114(1): 335-336. DOI: 10.1007/s00436-014-4228-7 [41] Huang W, Choi R, Hulverson MA, et al.5-Aminopyrazole-4-Carboxamide-based compounds prevent the growth of Cryptosporidium parvum[J]. Antimicrob Agents Chemother, 2017, 61: 8. DOI: 10.1128/AAC.00020-17 [42] Kuhlenschmidt TB, Rutaganira FU, Long S, et al.Inhibition of Calcium-Dependent Protein Kinase 1 (CDPK1) in vitro by pyrazolopyrimidine derivatives does not correlate with sensitivity of cryptosporidium parvum growth in cell culture[J]. Antimicrob Agents Chemother, 2015, 60(1): 570-579. DOI: 10.1128/AAC.01915-15 [43] Osman KT, Ye J, Shi Z, et al.Discovery and structure activity relationship of the first potent cryptosporidium FIKK kinase inhibitor[J]. Bioorg Med Chem, 2017, 25(5): 1672-1680. DOI: 10.1016/j.bmc.2017.01.036 [44] Manjunatha UH, Vinayak S, Zambriski JA, et al.A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis[J]. Nature, 2017, 546(7658): 376-380. DOI: 10.1038/nature22337 [45] Fritzler JM, Zhu G.Novel anti-Cryptosporidium activity of known drugs identified by high-throughput screening against parasite fatty acyl-CoA binding protein (ACBP)[J]. J Antimicrob Chemother, 2012, 67(3): 609-617. DOI: 10.1093/jac/dkr516 [46] Guo F, Zhang H, Fritzl er JM, et al. Ameliorationo Cryptosporidium parvum infection in vitro and in vivo by targeting parasite fatty acyl-co enzyme A synthetases[J]. J Infect Dis, 2014, 209(8): 1279-1287. DOI: 10.1093/infdis/jit645 [47] Sonzogni-Desautels K, Renteria AE, Camargo FV, et al.Oleylphosphocholine (OlPC) arrests Cryptosporidium parvum growth in vitro and prevents lethal infection in interferon gamma receptor knock-out mice[J]. Front Microbiol, 2015, 6: 973. DOI: 10.3389/fmicb.2015.00973 [48] Ndao M, Nath-Chowdhury M, Sajid M, et al.A cysteine protease inhibitor rescues mice from a lethal Cryptosporidium parvum infection[J]. Antimicrob Agents Chemother, 2013, 57(12): 6063-6073. DOI: 10.1128/AAC.00734-13 [49] Palencia A, Liu RJ, Lukarska M, et al.Cryptosporidium and Toxoplasma parasites are inhibited by a benzoxaborole targeting leucyl-trna synthetase[J]. Antimicrob Agents Chemother, 2016, 60(10): 5817-5827. DOI: 10.1128/AAC.00873-16 [50] Jain V, Yogavel M, Kikuchi H, et al. Targeting prolyl-trna synthetase to accelerate drug discovery against malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis,coccidiosis[J]. Structure, 2017, 25(10): 1495-1505.e6. DOI: 10.1016/j.str.2017.07.015 [51] Kumar VP, Cisneros JA, Frey KM, et al.Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase[J]. Bioorg Med Chem Lett, 2014, 24(17): 4158-4161. DOI: 10.1016/j.bmcl.2014.07.049 [52] Mukerjee A, Iyidogan P, Castellanos-Gonzalez A, et al.A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium[J]. Bioorg Med Chem Lett, 2015, 25(10): 2065-2067. DOI: 10.1016/j.bmcl.2015.03.091 [53] Jumani RS, Bessoff K, Love MS, et al. A novel piperazine-based drug lead for cryptosporidiosis from the medicines for malaria venture open access malaria box[J]. Antimicrob Agents Chemother, 2018, 62(4). pii:e01505-17. DOI: 10.1128/AAC.01505-17 [54] Stebbins E, Jumani RS, Klopfer C, et al.Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model[J]. PLoS Negl Trop Dis, 2018, 12(1): e0006183. DOI: 10.1371/journal.pntd.0006183 [55] Eltahan R, Guo F, Zhang H, et al.Discovery of ebselen as an inhibitor of Cryptosporidium parvum glucose-6-phosphate isomerase (CpGPI) by high-throughput screening of existing drugs[J]. Int J Parasitol Drugs Drug Resist, 2018, 8(1): 43-49. DOI: 10.1016/j.ijpddr.2018.01.003 [56] Jefferies R, Yang R, Woh CK, et al.Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer○R peptides[J]. Exp Parasitol, 2015, 148: 40-48. DOI: 10.1016/j.exppara.2014.11.003 [57] Gorla SK, McNair NN, Yang G, et al. Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis[J]. Antimicrob Agents Chemother, 2014, 58(3): 1603-1614. DOI: 10.1128/AAC.02075-13 [58] Dhal AK, Pani A, Mahapatra RK, et al.In-silico screening of small molecule inhibitors against Lactate Dehydrogenase (LDH) of Cryptosporidium parvum[J]. Comput Biol Chem, 2018, 77:44-51. DOI: 10.1016/j.compbiolchem.2018.09.002
