抗疟药研究进展

doi:10.12140/j.issn.1000-7423.2023.04.015

中国寄生虫学与寄生虫病杂志 ›› 2023, Vol. 41 ›› Issue (4): 486-491.doi: 10.12140/j.issn.1000-7423.2023.04.015

抗疟药研究进展

魏鸾葶¹(), 李润泽², 关良超², 张骞宇³, 李成⁴, 曹雅明⁴, 赵艳⁴^,^*()

1 中国医科大学中英联合学院，辽宁沈阳 110122
2 中国医科大学临床二系，辽宁沈阳 110122
3 中国医科大学临床一系，辽宁沈阳 110122
4 中国医科大学基础医学院免疫学教研室，辽宁沈阳 110122

收稿日期:2023-04-24 修回日期:2023-06-17 出版日期:2023-08-30 发布日期:2023-09-06
通讯作者: *赵艳（1990-），女，博士，副教授，从事抗感染免疫和疟疾分子流行病研究。E-mail：yzhao90@cmu.edu.cn
作者简介:魏鸾葶（2002-），女，本科生，从事免疫学方向研究。E-mail：W3395329716@163.com
基金资助:
国家自然科学基金(82002163)

Research progress of antimalarial drugs

WEI Luanting¹(), LI Runze², GUAN Liangchao², ZHANG Qianyu³, LI Cheng⁴, CAO Yaming⁴, ZHAO Yan⁴^,^*()

1 Queen's University Belfast Joint College, China Medical University, Shenyang 110122, Liaoning, China
2 The Second Clinical Department, China Medical University, Shenyang 110122, Liaoning, China
3 The First Clinical Department, China Medical University, Shenyang 110122, Liaoning, China
4 Department of Immunology, China Medical University, Shenyang 110122, Liaoning, China

Received:2023-04-24 Revised:2023-06-17 Online:2023-08-30 Published:2023-09-06
Contact: *E-mail: yzhao90@cmu.edu.cn
Supported by:
National Natural Science Foundation of China(82002163)

摘要/Abstract

摘要：

疟原虫的耐药性问题是药物治疗疟疾面临的最大挑战。疟原虫对包括青蒿素在内的常见传统抗疟药均产生了不同程度的耐药性，因此，传统药物的改进，以及对新型药物的研发刻不容缓。本文在系统地梳理传统抗疟药的耐药机制、传统药物的改进方法及优化成果和新型抗疟药研究进展的基础上，对疟疾防治策略进行讨论。

关键词: 抗疟药, 耐药性分析, 新药开发, 靶向药物, 防治策略

Abstract:

Antimalarial drug resistance presents the biggest challenge for treatment against malaria. Plasmodium parasites have developed different degrees of resistance to common traditional antimalarial drugs including artemisinin. Therefore, the improvement of traditional drugs and the research and development of new drugs are urgently needed. This paper discusses the malaria control strategies based on a systematic review of the resistance mechanisms against traditional antimalarial drugs, the improvement strategies and optimisation achievements based on traditional drugs, and the research advances of new antimalarial drugs.

Key words: Anti-malarial drugs, Drug resistance analysis, New drug development, Targeted drug, prevention strategy

中图分类号:

R531.3

魏鸾葶, 李润泽, 关良超, 张骞宇, 李成, 曹雅明, 赵艳. 抗疟药研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2023, 41(4): 486-491.

WEI Luanting, LI Runze, GUAN Liangchao, ZHANG Qianyu, LI Cheng, CAO Yaming, ZHAO Yan. Research progress of antimalarial drugs[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2023, 41(4): 486-491.

图/表 1

表1

传统抗疟药的特征与应用

治疗时期	药物名称	作用机制及优点	耐药机制及不足	应用现状	参考文献
红外期	伯氨喹	干扰疟原虫红外期能量代谢和呼吸作用，对间日疟原虫和卵形疟原虫的子孢子和配子体有杀灭作用，目前尚未发现耐药性。	不良反应明显，可导致红细胞减少，易发生溶血性贫血。	① 治疗耐氯喹的恶性疟原虫 ② 与青蒿素类药物联合使用具有根治作用	[9]
红外期	乙胺嘧啶	抑制二氢酸还原酶抑制细胞的分裂，抑制疟原虫繁殖，具有阻断作用。	二氢叶酸还原酶（Dihydrofolate Reductase，DHFR）S108N的突变导致耐药性产生，使用效果不佳。	① 常用于疟疾的预防与阻断传播 ② 与磺胺多辛联合用于防治耐氯喹的恶性疟	[10-11]
红内期	奎宁	第一种抗疟药，合成方式简单，可抑制有毒的血红素转化为聚合无毒的疟原虫色素，使虫体毒素储积过多死亡。	主要作用靶点为恶性疟原虫嘌呤核苷磷酸化酶的突变，导致耐药性产生，且药效低，不良反应较重。	① 在非洲部分地区治疗重症疟疾方面仍处于核心地位 ② 乌干达等部分非洲地区，治疗耐青蒿素疟原虫	[12-13]
	氯喹	与奎宁作用机制相似，干扰疟原虫繁殖，因具有长半衰期、高效力、低毒性的特点，代替奎宁成为治疗疟疾的首选药物。	氯喹抗性转运蛋白（Plasmodium falciparum chloroquine resistance transporter, Pfcrt）相关基因突变，导致氯喹无法进入疟原虫的消化液泡，无法发挥药效，导致患者病情反复。	① 主要治疗无并发症的恶性疟 ② 与其他药物联合使用	[14-15]
	苯芴醇	形成干扰血红素聚合的复合物，从而阻碍疟原虫裂殖子和配子体的发育，同时血浆半衰期较长，清除疟原虫彻底。	水溶性差，须与高脂肪食物共同服用以增强其在胃肠中的吸收，但这不适用于容易发生食欲不振、恶心、呕吐的疟疾患者；控制症状缓慢，病原虫复燃率高。	① 蒿甲醚-苯芴醇联合用药，增加了治疗疟疾的类型 ② 口服用药，每日仅需服药一次，方便治疗	[16]
	哌喹	作用机制类似于氯喹，半衰期长、消除缓慢，治疗后预防效果持续久。	天冬氨酸蛋白酶2（Plasmepsin2）基因扩增、Pfcrt基因突变等导致耐药性，哌喹单独使用时药效缓慢。	① 双氢青蒿素-哌喹（Dihydroar-temisinin-piperaquine, DHP）联合用药，使疗程缩短、起效加快，可治疗无并发症疟疾 ② 适用范围广，可有效治疗恶性疟和各种混合感染的疟疾	[17⇓⇓-20]
	阿莫地喹	可干扰疟原虫食物液泡中血红素的解毒，从而阻断其在血液阶段的发育，消除较慢。	恶性疟原虫多重抗药性蛋白1 （Plasmodium falciparum multidrug resistance protein 1, Pfmdr1）基因、Pfcrt基因突变导致耐药性，可产生多种不良反应，严重时出现肝损伤。	① 青蒿琥酯-阿莫地喹联合用药，广泛用于治疗单纯性疟疾 ② 清除原发性感染的恶性疟原虫	[21]
	青蒿素及其衍生物	在人体内代谢为二氢青蒿素，携带有过氧基团，被血红素裂解后产生大量氧自由基，使疟原虫营养代谢、免疫防御相关蛋白烷基化，具有安全性高、发挥效应快等优点。	恶性疟原虫Kelch蛋白13（Plasmodium falciparum Kelch protein 13, Pfk13）基因突变导致耐药性，半衰期短，导致患者病情反复。	以青蒿素为基础的联合疗法（atemisinin-based combination therapy，ACT），降低疟原虫产生耐药性的概率	[17⇓⇓⇓⇓-22]

表1

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抗疟药研究进展

Research progress of antimalarial drugs

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