常山酮抗原虫作用研究进展

doi:10.11843/j.issn.0366-6964.2023.03.007

摘要/Abstract

摘要： 寄生虫病是世界上最具破坏性和普遍性的传染病之一，造成每年数万人死亡的同时也导致巨大经济损失。常山酮(halofuginone)是从植物常山中分离提取的活性成分常山碱的卤代衍生物，具有强大的抗原虫活性。与常山碱相比，常山酮毒副作用更小的特点使其在疾病治疗上更有优势。近年来，常山酮在癌症、纤维化和自身免疫性疾病等方面的生物活性引起广泛关注。在人医临床上，常山酮针对杜兴氏肌肉营养不良症、实体瘤等的作用研究已进入临床试验阶段。在兽医临床上，常山酮氢溴酸盐和常山酮乳酸盐已分别被FDA和欧盟授权用于预防和治疗家禽球虫病和反刍动物隐孢子虫病。据报道，常山酮对疟原虫、弓形虫、泰勒虫、利什曼原虫等原虫的感染也有高效的治疗作用。氨酰-tRNA合成酶是寄生虫病治疗的新兴靶点，本文归纳总结了常山酮对多种原虫的作用以及抑制脯氨酰-tRNA合成酶的相关机制，以期为后续常山酮抗原虫的理论研究和临床应用提供参考依据。

关键词: 常山酮, 寄生虫病, 原虫, 脯氨酰-tRNA合成酶

Abstract: Parasitic diseases are the most destructive and pervasive infectious diseases in the world, killing tens of thousands of people annually and causing huge economic losses. Halofuginone is a halogenated derivative of febrifugine isolated and extracted from the plant Changshan, which has strong antiprotozoal activity. Compared with febrifugine, halofuginone has less toxic and side effects, which makes it more advantageous in disease treatment. In recent years, the biological activities of halofuginone in cancer, fibrosis and autoimmune diseases have attracted extensive attention. In human clinical practice, the research on the effects of halofuginone on Duchenne muscular dystrophy and solid tumors has entered the stage of clinical trials. In veterinary clinical practice, halofuginone hydrobromide and halofuginone lactate have been authorized by the FDA and the EU for the prevention and treatment of poultry coccidiosis and ruminant cryptosporidiosis, respectively. Moreover, halofuginone also has efficient inhibition on protozoa parasites such as Plasmodium, Toxoplasma, Theileria, and Leishmania. Aminoacyl-tRNA synthetases are emerging targets for the treatment of parasitic diseases, this review summarizes the effect of halofuginone on various protozoa parasites and the related mechanisms of inhibiting prolyl-tRNA synthetase, and hope to provide a reference for the subsequent theoretical research and clinical application of halofuginone antiprotozoal.

Key words: halofuginone, parasitic diseases, protozoa, prolyl-tRNA synthetase

中图分类号:

S859.795

林梦娟, 高沙沙, 赵星辰, 仲宇欣, 吴俊, 张军忍, 郭大伟. 常山酮抗原虫作用研究进展[J]. 畜牧兽医学报, 2023, 54(3): 924-933.

LIN Mengjuan, GAO Shasha, ZHAO Xingchen, ZHONG Yuxin, WU Jun, ZHANG Junren, GUO Dawei. Research Progress on Antiprotozoal Activity of Halofuginone[J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(3): 924-933.

参考文献 64

[1]	ALUM A, RUBINO J R, IJAZ M K. The global war against intestinal parasites-should we use a holistic approach?[J]. Int J Infect Dis, 2010, 14(9):e732-e738.
[2]	CHOI B, KIM B. Prevalence and risk factors of intestinal parasite infection among schoolchildren in the Peripheral Highland Regions of Huanuco, Peru[J]. Osong Public Health Res Perspect, 2017, 8(5):302-307.
[3]	KOTLOFF K L, NATARO J P, BLACKWELDER W C, 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.
[4]	KORPE P S, HAQUE R, GILCHRIST C, et al. Natural history of cryptosporidiosis in a longitudinal study of slum-dwelling bangladeshi children:association with severe malnutrition[J]. PLoS Negl Trop Dis, 2016, 10(5):e0004564.
[5]	PIPERAKI E T, TASSIOS P T. Parasitic infections:their position and impact in the postindustrial world[J]. Clin Microbiol Infect, 2016, 22(6):469-470.
[6]	ZHU S R, WANG J, CHANDRASHEKAR G, et al. Synthesis and evaluation of 4-quinazolinone compounds as potential antimalarial agents[J]. Eur J Med Chem, 2010, 45(9):3864-3869.
[7]	MCLAUGHLIN N P, EVANS P. Dihydroxylation of vinyl sulfones:stereoselective synthesis of (+)-and (-)-febrifugine and halofuginone[J]. J Org Chem, 2010, 75(2):518-521.
[8]	陈玲,朱焕星,李桂华,等.抗球虫药常山酮的研究与应用[J].黑龙江畜牧兽医, 2012(19):34-36.CHEN L, ZHU H X, LI G H, et al. The study and application of the anticoccidial halofuginone[J]. Heilongjiang Animal Science and Veterinary Medicine, 2012(19):34-36.(in Chinese)
[9]	中华人民共和国农业农村部公告第350号.新兽药注册证书[S].北京:中华人民共和国农业农村部, 2020.Announcement No. 350 of the Ministry of Agriculture and Rural Affairs of the People's Republic of China. New veterinary drug registration certificate[S]. Beijing:Ministry of Agriculture and Rural Affairs of the People's Republic of China, 2020.(in Chinese)
[10]	HUEBNER K D, JASSAL D S, HALEVY O, et al. Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone[J]. Am J Physiol Heart Circ Physiol, 2008, 294(4):H1550-H1561.
[11]	HALEVY O, NAGLER A, LEVI-SCHAFFER F, et al. Inhibition of collagen type I synthesis by skin fibroblasts of graft versus host disease and scleroderma patients:effect of halofuginone[J]. Biochem Pharmacol, 1996, 52(7):1057-1063.
[12]	MARTY P, CHATELAIN B, LIHOREAU T, et al. Halofuginone regulates keloid fibroblast fibrotic response to TGF-β induction[J]. Biomed Pharmacother, 2021, 135:111182.
[13]	DE JONGE M J A, DUMEZ H, VERWEIJ J, et al. Phase I and pharmacokinetic study of halofuginone, an oral quinazolinone derivative in patients with advanced solid tumours[J]. Eur J Cancer, 2006, 42(12):1768-1774.
[14]	KOON H B, FINGLETON B, LEE J Y, et al. Phase II AIDS malignancy consortium trial of topical halofuginone in AIDS-related Kaposi sarcoma[J]. J Acquir Immune Defic Syndr, 2011, 56(1):64-68.
[15]	SANDOVAL D R, CLAUSEN T M, NORA C, et al. The prolyl-tRNA synthetase inhibitor halofuginone inhibits SARS-CoV-2 infection[J/OL]. bioRxiv, 2021.[2023-01-01] https://www.biorxiv.org/content/10.1101/2021.03.22.436522v3.full.pdf.
[16]	MILNER JR D J. Malaria pathogenesis[J]. Cold Spring Harb Perspect Med, 2018, 8(1):a025569.
[17]	DERBYSHIRE E R, MAZITSCHEK R, CLARDY J. Characterization of Plasmodium liver stage inhibition by halofuginone[J]. ChemMedChem, 2012, 7(5):844-849.
[18]	JAIN V, KIKUCHI H, OSHIMA Y, et al. Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase[J]. J Struct Funct Genomics, 2014, 15(4):181-190.
[19]	GEARY T G, DIVO A A, JENSEN J B. Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture[J]. Am J Trop Med Hyg, 1989, 40(3):240-244.
[20]	KOEPFLI J B, MEAD J F, BROCKMAN JR J A. An alkaloid with high antimalarial activity from Dichroa febrifuga[J]. J Am Chem Soc, 1947, 69(7):1837.
[21]	DÓRÁNÉ H K, CLAUDER O. Alkaloides deriving from indolo (2, 3-c) quinazoline (3, 2-a) pyridine. II. Synthesis and analysis of rutecarpine carbonic acid[J]. Acta Pharm Hung, 1974, 80-82.
[22]	HERMAN J D, PEPPER L R, CORTESE J F, et al. The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs[J]. Sci Transl Med, 2015, 7(288):288ra77.
[23]	SNOW R W, GUERRA C A, NOOR A M, et al. The global distribution of clinical episodes of Plasmodium falciparum malaria[J]. Nature, 2005, 434(7030):214-217.
[24]	HERMAN J D, RICE D P, RIBACKE U, et al. A genomic and evolutionary approach reveals non-genetic drug resistance in malaria[J]. Genome Biol, 2014, 15(11):511.
[25]	KADYKALO S, ROBERTS T, THOMPSON M, et al. The value of anticoccidials for sustainable global poultry production[J]. Int J Antimicrob Agents, 2018, 51(3):304-310.
[26]	张德福.氢溴酸常山酮抗柔嫩艾美耳球虫作用研究[D].杭州:浙江大学, 2012.ZHANG D F. The study on the action of halofuginone hydrobromide against Eimeria tenella[D]. Hangzhou:Zhejiang University, 2012.(in Chinese)
[27]	MCQUISTION T E, MCDOUGALD L R. Anticoccidial activity of arprinocid and halofuginone[J]. Vet Parasitol, 1981, 9(1):27-33.
[28]	ZHANG D F, SUN B B, YUE Y Y, et al. Anticoccidial effect of halofuginone hydrobromide against Eimeria tenella with associated histology[J]. Parasitol Res, 2012, 111(2):695-701.
[29]	RAMADAN A, EL-SOOUD K A, EL-BAHY M M. Anticoccidial efficacy of toltrazuril and halofuginone against Eimeria tenella infection in broiler chickens in Egypt[J]. Res Vet Sci, 1997, 62(2):175-178.
[30]	GIBSON A R, STRIEPEN B. Cryptosporidium[J]. Curr Biol, 2018, 28(5):R193-R194.
[31]	BRAINARD J, HAMMER C C, HUNTER P R, et al. Efficacy of halofuginone products to prevent or treat cryptosporidiosis in bovine calves:a systematic review and meta-analyses[J]. Parasitology, 2021, 148(4):408-419.
[32]	JAIN V, YOGAVEL M, KIKUCHI H, et al. Targeting Prolyl-tRNA synthetase to accelerate drug discovery against malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis, and coccidiosis[J]. Structure, 2017, 25(10):1495-1505.
[33]	BARAGAÑA B, FORTE B, CHOI R, et al. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis[J]. Proc Natl Acad Sci U S A, 2019, 116(14):7015-7020.
[34]	VINAYAK S, JUMANI R S, MILLER P, et al. Bicyclic azetidines kill the diarrheal pathogen Cryptosporidium in mice by inhibiting parasite phenylalanyl-tRNA synthetase[J]. Sci Transl Med, 2020, 12(563):eaba8412.
[35]	LINDER M R, HECKEROTH A R, 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.
[36]	TROTZ-WILLIAMS L A, JARVIE B D, PEREGRINE A S, et al. Efficacy of halofuginone lactate in the prevention of cryptosporidiosis in dairy calves[J]. Vet Rec, 2011, 168(19):509.
[37]	SHAHIDUZZAMAN M, DYACHENKO V, OBWALLER A, et al. Combination of cell culture and quantitative PCR for screening of drugs against Cryptosporidium parvum[J]. Vet Parasitol, 2009, 162(3-4):271-277.
[38]	TROTZ-WILLIAMS L A, JARVIE B D, MARTIN S W, et al. Prevalence of Cryptosporidium parvum infection in southwestern Ontario and its association with diarrhea in neonatal dairy calves[J]. Can Vet J, 2005, 46(4):349-351.
[39]	PETERMANN J, PARAUD C, PORS I, et al. Efficacy of halofuginone lactate against experimental cryptosporidiosis in goat neonates[J]. Vet Parasitol, 2014, 202(3-4):326-329.
[40]	GAȽECKI R, SOKÓȽ R. Treatment of cryptosporidiosis in captive green iguanas (Iguana iguana)[J]. Vet Parasitol, 2018, 252:17-21.
[41]	VÁLEZ J, LANGE M K, ZIEGER P, et al. Long-term use of yeast fermentation products in comparison to halofuginone for the control of cryptosporidiosis in neonatal calves[J]. Vet Parasitol, 2019, 269:57-64.
[42]	ALMAWLY J, PRATTLEY D, FRENCH N P, et al. Utility of halofuginone lactate for the prevention of natural cryptosporidiosis of calves, in the presence of co-infection with rotavirus and Salmonella Typhimurium[J]. Vet Parasitol, 2013, 197(1-2):59-67.
[43]	ROBERT-GANGNEUX F, DARDÉ M L. Epidemiology of and diagnostic strategies for toxoplasmosis[J]. Clin Microbiol Rev, 2012, 25(2):264-296.
[44]	MANICKAM Y, MALHOTRA N, MISHRA S, et al. Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development[J]. PLoS Pathog, 2022, 18(3):e1010363.
[45]	YOUNG K M, CORRIN T, WILHELM B, et al. Zoonotic Babesia:a scoping review of the global evidence[J]. PLoS One, 2019, 14(12):e0226781.
[46]	ZWEYGARTH E, AHMED J S, REHBEIN G. The effect of halofuginone, Wellcome 993 C, oxytetracycline, and diminazene diaceturate on Babesia equi-infected lymphoblastoid cell cultures[J]. J Parasitol, 1984, 70(4):542-544.
[47]	WATTS J G, PLAYFORD M C, HICKEY K L. Theileria orientalis:a review[J]. N Z Vet J, 2016, 64(1):3-9.
[48]	DE VOS A J, ROOS J A, BIGALKE R D. Chemotherapy of Theileria parva lawrencei infections in cattle with halofuginone[J]. Onderstepoort J Vet Res, 1983, 50(1):33-35.
[49]	KILTZ H H, HUMKE R. Bovine theileriosis in Burundi:chemotherapy with halofuginone lactate[J]. Trop Anim Health Prod, 1986, 18(3):139-145.
[50]	DOLAN T T. Chemotherapy of East Coast fever. Treatment of infections induced by isolates of Theileria parva with halofuginone[J]. Acta Trop, 1986, 43(2):165-173.
[51]	MEHLHORN H, MOLTMANN U, SCHEIN E, et al. Electron microscopical study on the effect of halofuginone on Theileria parva[J]. Tropenmed Parasitol, 1981, 32(4):231-233.
[52]	POSTIGO J A R. Leishmaniasis in the world health organization eastern Mediterranean region[J]. Int J Antimicrob Agents, 2010, 36(S1):S62-S65.
[53]	DATTA A, PODDER I, DAS A, et al. Therapeutic modalities in post Kala-azar dermal leishmaniasis:a systematic review of the effectiveness and safety of the treatment options[J]. Indian J Dermatol, 2021, 66(1):34-43.
[54]	PRINSLOO I F, ZUMA N H, AUCAMP J, et al. Synthesis and in vitro antileishmanial efficacy of novel quinazolinone derivatives[J]. Chem Biol Drug Des, 2021, 97(2):383-398.
[55]	KELLER T L, ZOCCO D, SUNDRUD M S, et al. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase[J]. Nat Chem Biol, 2012, 8(3):311-317.
[56]	MISHRA S, MALHOTRA N, KUMARI S, et al. Conformational heterogeneity in apo and drug-bound structures of Toxoplasma gondii prolyl-tRNA synthetase[J]. Acta Crystallogr F Struct Biol Commun, 2019, 75(Pt 11):714-724.
[57]	葛俊驿,邱晓挺,金海晓.氨酰tRNA合成酶作用机制及其应用[J].中国生物化学与分子生物学报, 2017, 33(1):22-29.GE J Y, QIU X T, JIN H X. Aminoacyl-tRNA synthetase acting mechanism and its applications[J]. Chinese Journal of Biochemistry and Molecular Biology, 2017, 33(1):22-29.(in Chinese)
[58]	HURDLE J G, O'NEILL A J, INGHAM E, et al. Analysis of mupirocin resistance and fitness in Staphylococcus aureus by molecular genetic and structural modeling techniques[J]. Antimicrob Agents Chemother, 2004, 48(11):4366-4376.
[59]	BAKER S J, ZHANG Y K, AKAMA T, et al. Discovery of a new boron-containing antifungal agent, 5-fluoro-1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole (AN2690), for the potential treatment of onychomycosis[J]. J Med Chem, 2006, 49(15):4447-4450.
[60]	BHATT T K, KAPIL C, KHAN S, et al. A genomic glimpse of aminoacyl-tRNA synthetases in malaria parasite Plasmodium falciparum[J]. BMC Genomics, 2009, 10(1):644.
[61]	ZHOU H H, SUN L T, YANG X L, et al. ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase[J]. Nature, 2013, 494(7435):121-124.
[62]	SUNDRUD M S, KORALOV S B, FEUERER M, et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response[J]. Science, 2009, 324(5932):1334-1338.
[63]	GUO J S, CHEN B Y, YU Y, et al. Discovery of novel tRNA-amino acid dual-site inhibitors against threonyl-tRNA synthetase by fragment-based target hopping[J]. Eur J Med Chem, 2020, 187:111941.
[64]	HEWITT S N, DRANOW D M, HORST B G, et al. Biochemical and structural characterization of selective allosteric inhibitors of the Plasmodium falciparum drug target, Prolyl-tRNA-synthetase[J]. ACS Infect Dis, 2017, 3(1):34-44.