Department of Pediatrics, Section of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
PLoS Negl Trop Dis. 2012;6(7):e1680. doi: 10.1371/journal.pntd.0001680. Epub 2012 Jul 3.
Hookworm disease is a major global health problem and principal among a number of soil-transmitted helminthiases (STHs) for the chronic disability inflicted that impacts both personal and societal productivity. Mass drug administration most often employs single-dose therapy with just two drugs of the same chemical class to which resistance is a growing concern. New chemical entities with the appropriate single-dose efficacy are needed.
Using various life-cycle stages of the hookworm Ancylostoma ceylanicum in vitro and a hamster model of infection, we report the potent, dose-dependent cidal activities of the peptidyl cysteine protease inhibitors (CPIs) K11002 (4-mopholino-carbonyl-phenylalanyl-homophenylalanyl- vinyl sulfone phenyl) and K11777 (N-methylpiperazine-phenylalanyl-homophenylalanyl-vinylsulfone phenyl). The latter is in late pre-clinical testing for submission as an Investigational New Drug (IND) with the US Federal Drug Administration as an anti-chagasic. In vitro, K11002 killed hookworm eggs but was without activity against first-stage larvae. The reverse was true for K11777 with a larvicidal potency equal to that of the current anti-hookworm drug, albendazole (ABZ). Both CPIs produced morbidity in ex vivo adult hookworms with the activity of K11777 again being at least the equivalent of ABZ. Combinations of either CPI with ABZ enhanced morbidity compared to single compounds. Strikingly, oral treatment of infected hamsters with 100 mg/kg K11777 b.i.d. (i.e., a total daily dose of 200 mg/kg) for one day cured infection: a single 100 mg/kg treatment removed >90% of worms. Treatment also reversed the otherwise fatal decrease in blood hemoglobin levels and body weights of hosts. Consistent with its mechanism of action, K11777 decreased by >95% the resident CP activity in parasites harvested from hamsters 8 h post-treatment with a single 100 mg/kg oral dose.
A new, oral single-dose anthelmintic that is active in an animal model of hookworm infection and that possesses a distinct mechanism of action from current anthelmintics is discovered. The data highlight both the possibility of repurposing the anti-chagasic K11777 as a treatment for hookworm infection and the opportunity to further develop CPIs as a novel anthelmintic class to target hookworms and, possibly, other helminths.
钩虫病是一个全球性的主要健康问题，也是许多土壤传播性蠕虫病（STHs）中的主要疾病之一，因为它会导致慢性残疾，从而影响个人和社会的生产力。大规模药物治疗通常采用单一剂量疗法，仅使用两种相同化学类别的药物，而这些药物的耐药性日益受到关注。需要具有适当单剂量疗效的新化学实体。
我们使用钩虫Ancylostoma ceylanicum 的各种生活史阶段和仓鼠感染模型，报告了肽基半胱氨酸蛋白酶抑制剂（CPIs）K11002（4-吗啉羰基-苯丙氨酰-同苯丙氨酰-乙烯基砜苯）和 K11777（N-甲基哌嗪-苯丙氨酰-同苯丙氨酰-乙烯基砜苯）的有效、剂量依赖性杀幼虫活性。后者正在进行后期临床前试验，准备作为一种新药（IND）向美国食品和药物管理局提交，作为一种抗恰加斯病药物。在体外，K11002 杀死钩虫卵，但对第一阶段幼虫没有活性。相反，K11777 对幼虫具有杀幼虫作用，其效力与目前的抗钩虫药物阿苯达唑（ABZ）相当。两种 CPIs 都能引起离体成年钩虫的发病，K11777 的活性再次至少与 ABZ 相当。ABZ 与 ABZ 联合使用可提高发病率。引人注目的是，口服治疗感染仓鼠 100mg/kg K11777 每天两次（即每天总剂量 200mg/kg）一天即可治愈感染：单次 100mg/kg 治疗即可清除>90%的蠕虫。治疗还逆转了宿主血液血红蛋白水平和体重下降的致命情况。与作用机制一致，K11777 在仓鼠中单次 100mg/kg 口服剂量后 8 小时处理时，可使寄生虫中驻留的 CP 活性降低>95%。
发现了一种新的、口服单剂量驱虫药，在钩虫感染的动物模型中具有活性，并且具有与现有驱虫药不同的作用机制。数据突出了将抗恰加斯病药物 K11777 重新用作钩虫感染治疗的可能性，以及进一步开发 CPIs 作为一种新型驱虫药类别来针对钩虫和可能的其他蠕虫的机会。
