Stepek G, Lowe A E, Buttle D J, Duce I R, Behnke J M
School of Biology, University Park, University of Nottingham, Nottingham NG7 2RD, UK.
Parasitology. 2007 Sep;134(Pt 10):1409-19. doi: 10.1017/S0031182007002867. Epub 2007 May 3.
Gastrointestinal (GI) nematodes are important disease-causing organisms, controlled primarily through treatment with synthetic drugs, but the efficacy of these drugs has declined due to widespread resistance, and hence new drugs, with different modes of action, are required. Some medicinal plants, used traditionally for the treatment of worm infections, contain cysteine proteinases known to damage worms irreversibly in vitro. Here we (i) confirm that papaya latex has marked efficacy in vivo against the rodent gastrointestinal nematode, Heligmosomoides polygyrus, (ii) demonstrate the dose-dependent nature of the activity (>90% reduction in egg output and 80% reduction in worm burden at the highest active enzyme concentration of 133 nmol), (iii) establish unequivocally that it is the cysteine proteinases that are the active principles in vivo (complete inhibition of enzyme activity when pre-incubated with the cysteine proteinase-specific inhibitor, E-64) and (iv) show that activity is confined to worms that are in the intestinal lumen. The mechanism of action was distinct from all current synthetic anthelmintics, and was the same as that in vitro, with the enzymes attacking and digesting the protective cuticle. Treatment had no detectable side-effects on immune cell numbers in the mucosa (there was no difference in the numbers of mast cells and goblet cells between the treated groups) and mucosal architecture (length of intestinal villi). Only the infected and untreated mice had much shorter villi than the other 3 groups, which was a consequence of infection and not treatment. Plant-derived cysteine proteinases are therefore prime candidates for development as novel drugs for the treatment of GI nematode infections.
胃肠道线虫是重要的致病生物，主要通过使用合成药物进行控制，但由于广泛存在的抗药性，这些药物的疗效已经下降，因此需要具有不同作用方式的新药。一些传统上用于治疗蠕虫感染的药用植物含有半胱氨酸蛋白酶，已知这些酶在体外会对蠕虫造成不可逆的损害。在这里，我们（i）证实木瓜乳胶在体内对啮齿动物胃肠道线虫多毛螺旋线虫具有显著疗效，（ii）证明了活性的剂量依赖性（在最高活性酶浓度为133 nmol时，产卵量减少>90%，虫体负荷减少80%），（iii）明确确定半胱氨酸蛋白酶是体内的活性成分（与半胱氨酸蛋白酶特异性抑制剂E-64预孵育时，酶活性完全被抑制），并且（iv）表明活性仅限于肠腔内的蠕虫。其作用机制与目前所有的合成驱虫药不同，与体外情况相同，即这些酶攻击并消化保护性角质层。治疗对黏膜中的免疫细胞数量（治疗组之间肥大细胞和杯状细胞数量没有差异）和黏膜结构（肠绒毛长度）没有可检测到的副作用。只有感染且未治疗的小鼠的绒毛比其他三组短得多，这是感染的结果而非治疗的结果。因此，植物源半胱氨酸蛋白酶是开发用于治疗胃肠道线虫感染的新型药物的主要候选物。
