抗菌肽的抗疟原虫活性及作用机制的研究进展

摘要/Abstract

摘要：

抗菌肽是广泛存在于生物体内的一类小分子多肽,是生物固有免疫系统的重要组成部分。抗菌肽能够有效杀灭细菌,对真菌、病毒、寄生虫甚至肿瘤细胞也有一定的杀伤作用。研究证实,抗菌肽可通过基于细胞膜的膜攻击以及胞内杀伤两种机制抑制不同阶段疟原虫的生长,且疟原虫对抗菌肽不易产生耐药性,使其具有重要的抗疟价值。目前,被分离和鉴定的具有抗疟作用的抗菌肽有多种,其中作用于疟原虫红细胞内期的抗菌肽有dermaseptins及其衍生物dermaseptin S3、dermaseptin S4,天蚕素B及其衍生物SB-37、Shiva-1,防御素DefMT2、DefMT3与DefMT5等;作用于疟原虫有性生殖阶段的抗菌肽主要有duramycin、蜂毒肽、TP10与Vida1~Vida3等。本文综述了近年来有关抗菌肽对疟原虫的抑制作用及其抗疟原虫机制的研究进展。

关键词: 抗菌肽, 疟原虫, 作用机制, 抗疟药

Abstract:

Antimicrobial peptides (AMPs) consist of a diverse group of small molecular polypeptides that widely exist in organisms and act as an important part of the innate immune system. AMPs can not only effectively kill bacteria, but also kill fungi, viruses, parasites and even tumor cells. It has been proved that antimicrobial peptides can inhibit the growth of different stages of Plasmodium protozoan and no drug tolerance has been identified so far, making it valuable as a novel anti-malaria agent. Currently, a variety of AMPs with anti-malarial activities have been successively isolated and identified. It includes the AMPs that target Plasmodium within erythrocytes such as dermaseptins and their derivatives dermaseptin S3 and dermaseptin S4, cecropin B and its derivatives SB-37 and Shiva-1, Defensin DefMT2, DefMT3 and DefMT5, etc. Those AMPs targeting the sexual stage of Plasmodium mainly include duramycin, melittin, TP10 and Vida1-Vida3. In this paper, the inhibition effects of AMPs on different developmental stages of Plasmodium and the possible mechanisms are reviewed.

Key words: Antimicrobial peptide, Plasmodium, Mechanism, Anti-malaria agent

中图分类号:

R978.613

郑文琪, 苏秀兰. 抗菌肽的抗疟原虫活性及作用机制的研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2018, 36(6): 643-647.

Wen-qi ZHENG, Xiu-lan SU. Anti-Plasmodium activity and mechanisms of antimicrobial peptides[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2018, 36(6): 643-647.

图/表 2

表1

表2

参考文献 45

[1]	World Health Organization.World Malaria Report 2017[R]. Geneva: WHO, 2017.
[2]	World Health Organization.Global technical strategy for malaria 2016-2030[R]. Geneva: WHO, 2015.
[3]	雷正龙, 王立英. 全国重点寄生虫病防治形势与主要任务[J]. 中国寄生虫学与寄生虫病杂志, 2012, 30(1): 1-5.
[4]	张丽, 丰俊, 夏志贵. 2013年全国疟疾疫情分析[J]. 中国寄生虫学与寄生虫病杂志, 2014, 32(6): 407-413.
[5]	丰俊, 张丽, 周水森, 等. 全国2005-2015年疟疾疫情分析[J]. 中国热带医学, 2017, 17(4): 325-334.
[6]	张丽, 丰俊, 张少森, 等. 2017 年全国消除疟疾进展及疫情特征分析[J]. 中国寄生虫学与寄生虫病杂志, 2018, 36(3): 201-209.
[7]	Cowman AF, Healer J, Marapana D, et al. Malaria: biology and disease[J]. Cell, 2016, 167(3): 610-624.
[8]	Sinha S, Medhi B, Sehgal R.Challenges of drug-resistant malaria[J]. Parasite, 2014, 21: 61.
[9]	Draper SJ, Sack BK, King CR, et al. Malaria vaccines: recent advances and new horizons[J]. Cell Host Microbe, 2018, 24(1): 43-56.
[10]	Long CA, Zavala F.Malaria vaccines and human immune responses[J]. Curr Opin Microbiol, 2016, 32: 96-102.
[11]	Boman HG.Antibacterial peptides: key components needed in immunity[J]. Cell, 1991, 65(2): 205-207.
[12]	Hultmark D, Steiner H, Rasmuson T, et al. Insect immunity. Purification and properties of three inducible bactericidal proteins from hemolymph of immunized pupae of Hyalophora cecropia[J]. Eur J Biochem, 1980, 106(1): 7-16.
[13]	Steiner H, Hultmark D, Engström A, et al. Sequence and specificity of two antibacterial proteins involved in insect immunity[J]. Nature, 1981, 292(5820): 246-248.
[14]	Hancock RE.Peptide antibiotics[J]. Lancet, 1997, 349(9049): 418-422.
[15]	Jenssen H, Hamill P, Hancock RE.Peptide antimicrobial agents[J]. Clin Microbiol Rev, 2006, 19(3): 491-511.
[16]	Karstad R, Isaksen G, Wynendaele E, et al. Targeting the S1 and S3 subsite of trypsin with unnatural cationic amino acids generates antimicrobial peptides with potential for oral administration[J]. J Med Chem, 2012, 55(14): 6294-6305.
[17]	Gwadz RW, Kaslow D, Lee JY, et al. Effects of magainins and cecropins on the sporogonic development of malaria parasites in mosquitoes[J]. Infect Immun, 1989, 57(9): 2628-2633.
[18]	Vale N, Aguiar L, Gomes P.Antimicrobial peptides: a new class of antimalarial drugs[J]. Front Pharmacol, 2014, 5: 275.
[19]	Zairi A, Tangy F, Bouassida K, et al. Dermaseptins and magainins: antimicrobial peptides from frogs’ skin-new sources for a promising spermicides microbicides-a mini review[J]. J Biomed Biotechnol, 2009, 2009: 452567.
[20]	Ghosh JK, Shaool D, Guillaud P, et al. Selective cytotoxicity of dermaseptin S3 toward intraerythrocytic Plasmodium falciparum and the underlying molecular basis[J]. J Biol Chem, 1997, 272(50): 31609-31616.
[21]	Krugliak M, Feder R, Zolotarev VY, et al. Antimalarial activities of dermaseptin S4 derivatives[J]. Antimicrob Agents Chemother, 2000, 44(9): 2442-2451.
[22]	Efron L, Dagan A, Gaidukov L, et al. Direct interaction of dermaseptin S4 aminoheptanoyl derivative with intraerythrocytic malaria parasite leading to increased specific antiparasitic activity in culture[J]. J Biol Chem, 2002, 277(27): 24067-24072.
[23]	Jaynes JM, Burton CA, Barr SB, et al. In vitro cytocidal effect of novel lytic peptides on Plasmodium falciparum and Trypanosoma cruzi[J]. FASEB J, 1988, 2(13): 2878-2883.
[24]	Cabezas-Cruz A, Tonk M, Bouchut A, et al. Antiplasmodial activity is an ancient and conserved feature of tick defensins[J]. Front Microbiol, 2016, 7: 1682.
[25]	Couto J, Tonk M, Ferrolho J, et al. Antiplasmodial activity of tick defensins in a mouse model of malaria[J]. Ticks Tick Borne Dis, 2018, 9(4): 844-849.
[26]	Carter V, Hurd H.Choosing anti-Plasmodium molecules for genetically modifying mosquitoes: focus on peptides[J]. Trends Parasitol, 2010, 26(12): 582-590.
[27]	Sinden RE, Dawes EJ, Alavi Y, et al. Progression of Plasmodium berghei through Anopheles stephensi is density-dependent[J]. PLoS Pathog, 2007, 3(12): e195.
[28]	Tian C, Gao B, Rodriguez Mdel C, et al. Gene expression, antiparasitic activity, and functional evolution of the drosomycin family[J]. Mol Immunol, 2008, 45(15): 3909-3916.
[29]	Carter V, Underhill A, Baber I, et al. Killer bee molecules: antimicrobial peptides as effector molecules to target sporogonic stages of Plasmodium[J]. PLoS Pathog, 2013, 9(11): e1003790.
[30]	Fredenhagen A, Fendrich G, Märki F, et al. Duramycins B and C, two new lanthionine containing antibiotics as inhibitors of phospholipase A2. Structural revision of duramycin and cinnamycin[J]. J Antibiot, 1990, 43(11): 1403-1412.
[31]	Asthana N, Yadav SP, Ghosh JK.Dissection of antibacterial and toxic activity of melittin: a leucine zipper motif plays a crucial role in determining its hemolytic activity but not antibacterial activity[J]. J Biol Chem, 2004, 279(53): 55042-55050.
[32]	Arrighi RB, Ebikeme C, Jiang Y, et al. Cell-penetrating peptide TP10 shows broad-spectrum activity against both Plasmodium falciparum and Trypanosoma brucei brucei[J]. Antimicrob Agents Chemother, 2008, 52(9): 3414-3417.
[33]	Arrighi RB, Nakamura C, Miyake J, et al. Design and activity of antimicrobial peptides against sporogonic-stage parasites causing murine malarias[J]. Antimicrob Agents Chemother, 2002, 46(7): 2104-2110.
[34]	Konno K, Hisada M, Fontana R, et al. Anoplin, a novel antimicrobial peptide from the venom of the solitary wasp Anoplius samariensis[J]. Biochim Biophys Acta, 2001, 1550(1): 70-80.
[35]	Longland CL, Mezna M, Michelangeli F.The mechanism of inhibition of the Ca2+-ATPase by mastoparan. Mastoparan abolishes cooperative Ca2+ binding[J]. J Biol Chem, 1999, 274(21): 14799-14805.
[36]	Vizioli J, Bulet P, Hoffmann JA, et al. Gambicin: a novel immune responsive antimicrobial peptide from the malaria vector Anopheles gambiae[J]. Proc Natl Acad Sci USA, 2001, 98(22): 12630-12635.
[37]	Rodriguez MC, Zamudio F, Torres JA, et al. Effect of a cecropin-like synthetic peptide (Shiva-3) on the sporogonic development of Plasmodium berghei[J]. Exp Parasitol, 1995, 80(4): 596-604.
[38]	Conde R, Zamudio FZ, Rodríguez MH, et al. Scorpine, an anti-malaria and anti-bacterial agent purified from scorpion venom[J]. FEBS Lett, 2000, 471(2-3): 165-168.
[39]	Biswaro LS, da Costa Sousa MG, Rezende TMB, et al. Antimicrobial peptides and nanotechnology, recent advances and challenges[J]. Front Microbiol, 2018, 9: 855.
[40]	Hsiao LL, Howard RJ, Aikawa M, et al. Modification of host cell membrane lipid composition by the intra-erythrocytic human malaria parasite Plasmodium falciparum[J]. Biochem J, 1991, 274(Pt 1): 121-132.
[41]	Gelhaus C, Jacobs T, Andrä J, et al. The antimicrobial peptide NK-2, the core region of mammalian NK-lysin, kills intraerythrocytic Plasmodium falciparum[J]. Antimicrob Agents Chemother, 2008, 52(5): 1713-1720.
[42]	Park Y, Hahm KS.Antimicrobial peptides(AMPs): peptide structure and mode of action[J]. J Biochem Mol Biol, 2005, 38(5): 507-516.
[43]	Harms JM, Wilson DN, Schluenzen F, et al. Translational regulation via L11: molecular switches on the ribosome turned on and off by thiostrepton and micrococcin[J]. Mol Cell, 2008, 30(1): 26-38.
[44]	Azevedo R, Markovic M, Machado M, et al. Bioluminescence method for in vitro screening of Plasmodium transmission-blocking compounds[J]. Antimicrob Agents Chemother, 2017, 61(6): e02699-16.
[45]	Aminake MN, Schoof S, Sologub L, et al. Thiostrepton and derivatives exhibit antimalarial and gametocytocidal activity by dually targeting parasite proteasome and apicoplast[J]. Antimicrob Agents Chemother, 2011, 55(4): 1338-1348.

抗菌肽	氨基酸序列	来源	作用阶段与特点
CA(1~13)M(1~13)	KWKLFKKIEKVGQGIGA- VLKVLTTGL	天蚕素与蜂毒肽混合	杀伤红细胞内期的恶性疟原虫^[18]
Dermaseptin DS3	X-ALWKNMLKGIGKLAG- KAALGAVKKLVGAES	索瓦叶泡蛙 Phyllomedusa sauvagii Dermaseptin 衍生物	杀伤红细胞内期的恶性疟原虫^[20]
Dermaseptin DS4	X-ALWMTLLKKVLKAAA- KAALNAVLVGANA	索瓦叶泡蛙 Phyllomedusa sauvagii Dermaseptin 衍生物	杀伤红细胞内期的恶性疟原虫^[21]
Dermaseptin K4K20-S4	ALWKTLLKKVLKAAAK- AALKAVLVGANA	索瓦叶泡蛙 Phyllomedusa sauvagii Dermaseptin S4 衍生物	杀伤红细胞内期的恶性疟原虫^[21]
Dermaseptin K4-S4	ALWMTLLKKVLKA-NH2	索瓦叶泡蛙 Phyllomedusa sauvagii dermaseptin S4 derivative	杀伤红细胞内期的恶性疟原虫^[21]
Dermaseptin NC7-P	H2N-(CH2)6-CO-ALWKTLL- KKVLKA-NH2	索瓦叶泡蛙 Phyllomedusa sauvagii dermaseptin K4-S4(1~13)a 衍生物	杀伤红细胞内期的恶性疟原虫^[22]
SB-37	MPKWKVFKKIEKVGRNIRN- GIVKAGPAIAVLGEAKALG	合成的天蚕素B衍生物	杀伤红细胞内期的恶性疟原虫^[23]
Shiva-1	MPRWRLFRRIDRVGKQIKQ- GILRAGPAIALVGDARAVG	合成的天蚕素B衍生物	杀伤红细胞内期的恶性疟原虫^[23]
DefMT2	GYFCPYNGYCDHHCRKKLRWRGGYCGGRWKLTCICVRG	蓖子硬蜱 Ixodes ricinus	杀伤红细胞内期的恶性疟原虫和夏氏疟原虫^[24,25]
DefMT5	GFFCPYNGYCDRHCRKKLRRRGGYCGGRWKLTCICIMN	蓖子硬蜱 Ixodes ricinus	杀伤红细胞内期的恶性疟原虫和夏氏疟原虫^[24,25]

抗菌肽名称	氨基酸序列	来源	作用阶段与特点
Drosomycin	DCLSGRYKGPCAVWDNETCRRVCKEEGRSSGHCSPSLKCWCEGC	黑腹果蝇	抑制伯氏疟原虫配子体的形成^[28]
Anoplin	GLLKRIKTLLNH2	黄蜂	抑制伯氏疟原虫动合子的形成^{[29, 34]}
天蚕素B	KWKVFKKIEKMGRNIRNGIVKAGPAIAVLGEAKALG	刻克罗普斯蚕蛾	抑制疟原虫卵囊的形成^[17]
防御素A	ATCDLLSGFGVGDSACAAHCIARGNRGGYCNSKKVCVCRN	埃及伊蚊	抑制鸡疟原虫卵囊的形成^[39]
Gambicin	MVFAYAPTXARXKSIGARYXGYGYLNRK- GVSXDGQTTINSXEDXKRKFGRXSDGFIT	冈比亚按蚊	抑制伯氏疟原虫动合子的形成^[36]
蜂毒肽	X-NH-GIGAVLKVLTTGLPALISWIKRKR- QQCONH2	蜜蜂	抑制伯氏疟原虫动合子的形成^[31]
Mastoparan X	INLKALAALAKKIL	黄蜂	抑制伯氏疟原虫动合子的形成^{[29, 35]}
蛙皮素2	GIGKFLHSAKKFGKAFVGEIMNS	非洲爪蟾	抑制疟原虫动合子的形成^[29]
TP10 (二聚体)	AGYLLGKINLKALAALAKKIL	黄蜂	抑制伯氏疟原虫动合子的形成,抑制恶性疟原虫卵囊的形成^[32]
Vida1	KWKKFKKGIGKLFV	合成的天蚕素B/蜂毒肽衍生物	抑制伯氏疟原虫动合子的形成^[33]
Vida2	KWPKFKKGIPWLFV	合成的天蚕素B/蜂毒肽衍生物	抑制伯氏疟原虫动合子的形成^[33]
Vida3	KWPKFRRGIPFLFV	合成的天蚕素B/蜂毒肽衍生物	抑制伯氏疟原虫动合子的形成^{[29, 33]}
Shiva-1	MPRWRLFRRIDRVGKQIKQGILRAGPAIALVGDARAVG	合成的天蚕素B 衍生物	抑制伯氏疟原虫动合子与早期子孢子的形成^[37]
Scorpine	GWINEEKIQKKIDERMGNTVLGGMAK- AIVHKMAKNEFQCMANMDMLGNCEK- HCQTSGEKGYCHGTKCKCGTPLSY	非洲帝王蝎	抑制伯氏疟原虫动合子的形成^[38]