Schistosomiasis mansoni: novel chemotherapy using a cysteine protease inhibitor.
Schistosomiasis mansoni: novel chemotherapy using a cysteine protease inhibitor.
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DOI：
10.1371/journal.pmed.0040014
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发表时间：
2007-01
期刊：
影响因子：
15.8
通讯作者：
Caffrey CR
中科院分区：
文献类型：
--
作者：
Abdulla MH;Lim KC;Sajid M;McKerrow JH;Caffrey CR
血吸虫病是一种慢性、使人衰弱的寄生虫病，感染超过 2 亿人，在公共卫生重要性方面仅次于疟疾。由于缺乏疫苗，患者的治疗严重依赖世界卫生组织推荐药物吡喹酮化疗，但对耐药性的担忧鼓励寻找新的药物先导药物。在曼氏血吸虫鼠模型中测试了乙烯基砜半胱氨酸蛋白酶抑制剂 K11777 的功效。测量的疾病参数包括蠕虫和虫卵负荷以及器官病理学，包括肝和脾肿大、肝脏中是否存在寄生虫虫卵诱导的肉芽肿，以及作为肝细胞功能标志的循环丙氨酸转氨酶活性水平。 K11777（25 mg/kg，每日两次 [BID]）在寄生虫通过皮肤和肺部迁移时（感染后第 1-14 天 [p.i.]）腹腔内给药，使 7 例病例中的 5 例获得寄生虫学治愈（消除寄生虫卵），并解决其他疾病参数。 K11777（50 mg/kg BID），在成熟寄生虫产卵开始时（注射后第 30-37 天）施用，可减少蠕虫和卵的负担，并改善器官病理学。使用蛋白酶类特异性底物和活性位点标记，K11777 的一个分子靶标被确定为肠道相关组织蛋白酶 B1 半胱氨酸蛋白酶，但不排除其他半胱氨酸蛋白酶靶标。在啮齿动物、狗和灵长类动物中，K11777 不具有致突变性，具有令人满意的安全性和药代动力学特征。这种乙烯基砜半胱氨酸蛋白酶抑制剂显着减少了寄生虫负担和病理学，验证了血吸虫半胱氨酸蛋白酶作为药物靶点的有效性，并为人类血吸虫病化疗提供了新方向的潜力。乙烯基砜半胱氨酸蛋白酶抑制剂显着降低了寄生虫负荷和病理学，这为人类血吸虫病化疗提供了新方向。血吸虫病是一种由一种生活在血液中的寄生扁虫引起的疾病，感染全世界约 2 亿人。这种疾病是撒哈拉以南非洲、南美洲、中国和东南亚的一个严重问题。尽管这种疾病可以致命，但它更广为人知的是，它是一种终生慢性感染，具有使人衰弱的症状，主要是由于对肝脏、脾脏和肠道中滞留的寄生虫卵产生的免疫反应所致。这种蠕虫的生命周期很复杂，是一种自由游动的形式，是从生活在湖泊和池塘中的某些类型的蜗牛中产生的。它可以穿透与水接触的人的皮肤。在皮肤和肺部周围度过一段时间后，寄生虫会移动到肠道周围的静脉，并发育成成虫，交配并产卵。这些虫卵最终通过人的粪便或尿液回到水中。一组称为半胱氨酸蛋白酶的特殊蛋白质被认为在这些蠕虫的生物学中非常重要，特别是它们在寄生虫肠道中作为消化酶的功能。这些蛋白酶可能为开发治疗血吸虫病的新药提供令人兴奋的机会。研究人员正在研究是否有可能阻断半胱氨酸蛋白酶的活性，从而杀死蠕虫或阻止它们发育和繁殖。目前，只有一种药物常用来治疗血吸虫病，即吡喹酮。它既便宜又有效。然而，许多组织担心依靠单一药物来治疗影响全世界许多人的严重疾病。该研究小组一直在研究阻断半胱氨酸蛋白酶活性的分子，看看其中是否有任何一个可以成为治疗血吸虫病的良好候选药物。他们一直在研究一种名为 K11777 的分子，该分子正在作为另一种寄生虫感染（恰加斯病）的候选药物进行评估。在这里，研究人员想了解 K11777 是否具有对抗血吸虫的活性。在这项研究中，研究人员故意用血吸虫寄生虫感染实验室小鼠。然后，这些小鼠每天注射两次 K11777 溶液，或注射等量的水作为比较。研究人员检查了在感染“早期”（使用 14 天疗程，从感染寄生虫后 1 天开始）或“晚期”注射 K11777 的效果（使用感染后 30 天开始的 8 天疗程）。用于衡量 K11777 治疗成功与否的结果包括安乐死后从小鼠体内回收的蠕虫数量、肝脏中蠕虫卵的数量；肝脏受损的程度；最后，研究人员还研究了蠕虫本身的半胱氨酸蛋白酶的活性水平，特别是那些与寄生虫肠道相关的蛋白酶。早期处理实验的结果显示蠕虫数量和产卵量大幅下降。在接受治疗的七只小鼠中，有五只的卵子被完全消除。此外，几乎没有可测量的肝损伤。在后期治疗实验中，还发现K11777治疗小鼠肝脏中的蠕虫和虫卵负担减少，对肝脏的损害也较小。那些在治疗中幸存并从小鼠体内取出的蠕虫的肠道半胱氨酸蛋白酶活性也低得多，这表明 K11777 通过靶向蠕虫半胱氨酸蛋白酶来发挥其作用。这些实验表明 K11777 对小鼠来说是一种有效的抗血吸虫剂。因此，它可能是开发人类血吸虫病未来治疗方法的良好“候选”分子。然而，在达到这一阶段之前，开展临床试验来测试 K11777 对血吸虫病患者是否安全有效是很重要的。还需要确定哪种蠕虫半胱氨酸蛋白酶是 K11777 的关键靶标的详细信息，并且需要更多信息来了解是否可以减少本研究中使用的剂量计划（每周至 14 天每天注射两次）。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0040014。世界卫生组织有关血吸虫病的页面，包括进一步研究该疾病的详细信息的链接 美国疾病控制中心为患者和卫生专业人员提供有关血吸虫病的信息 维基百科有关血吸虫病的页面（维基百科是任何人都可以编辑的互联网百科全书） PLoS 被忽视的热带病是公共科学图书馆的一本新期刊，致力于发表有关世界上最被忽视的疾病的研究 热带疾病，包括血吸虫病
Schistosomiasis is a chronic, debilitating parasitic disease infecting more than 200 million people and is second only to malaria in terms of public health importance. Due to the lack of a vaccine, patient therapy is heavily reliant on chemotherapy with praziquantel as the World Health Organization–recommended drug, but concerns over drug resistance encourage the search for new drug leads. The efficacy of the vinyl sulfone cysteine protease inhibitor K11777 was tested in the murine model of schistosomiasis mansoni. Disease parameters measured were worm and egg burdens, and organ pathology including hepato- and splenomegaly, presence of parasite egg–induced granulomas in the liver, and levels of circulating alanine aminotransferase activity as a marker of hepatocellular function. K11777 (25 mg/kg twice daily [BID]), administered intraperitoneally at the time of parasite migration through the skin and lungs (days 1–14 postinfection [p.i.]), resulted in parasitologic cure (elimination of parasite eggs) in five of seven cases and a resolution of other disease parameters. K11777 (50 mg/kg BID), administered at the commencement of egg-laying by mature parasites (days 30–37 p.i.), reduced worm and egg burdens, and ameliorated organ pathology. Using protease class-specific substrates and active-site labeling, one molecular target of K11777 was identified as the gut-associated cathepsin B1 cysteine protease, although other cysteine protease targets are not excluded. In rodents, dogs, and primates, K11777 is nonmutagenic with satisfactory safety and pharmacokinetic profiles. The significant reduction in parasite burden and pathology by this vinyl sulfone cysteine protease inhibitor validates schistosome cysteine proteases as drug targets and offers the potential of a new direction for chemotherapy of human schistosomiasis. A significant reduction in parasite burden and pathology by a vinyl sulfone cysteine protease inhibitor suggests a new direction for chemotherapy of human schistosomiasis. Schistosomiasis, a disease caused by a type of parasitic flatworm that lives in the blood, infects around 200 million people worldwide. The disease is a serious problem in sub-Saharan Africa, South America, China, and southeast Asia. Although this disease can kill, it is better known as a lifelong chronic infection with debilitating symptoms mainly due to an immune reaction raised against parasite eggs trapped in the liver, spleen, and gut. The worm's life cycle is complicated and involves a free-swimming form that emerges from certain types of snails that live in lakes and ponds. This can penetrate the skin of people in contact with the water. After a period spent in the skin and around the lungs, the parasites move to veins around the gut, and develop into adult worms that mate and lay eggs. These eggs eventually return to the water through the person's feces or urine. A particular group of proteins called cysteine proteases are thought to be very important in the biology of these worms, especially in their function as digestive enzymes in the parasite's gut. These proteases could represent an exciting opportunity for development of new drugs to treat schistosomiasis. The researchers are looking at whether it is possible to block the activity of cysteine proteases and, as a result, kill the worms or prevent them from developing and thriving. At the moment there is only one drug, praziquantel, in common use for treatment of schistosomiasis; it is cheap and effective. However many organizations are worried about relying on a single drug to treat a serious disease which affects so many people worldwide. The research group here has been looking at molecules that block cysteine protease activity, to see if any of these could be good drug candidates for schistosomiasis. One molecule they have been looking at goes by the name of K11777, which is under evaluation as a drug candidate for another parasitic infection (Chagas' disease). Here, the researchers wanted to find out whether K11777 had any activity against schistosome worms. In this study, the researchers deliberately infected laboratory mice with the schistosome parasite. These mice were then either injected with K11777 solution twice daily, or with equivalent volumes of water as a comparison. The researchers examined the effects of injecting K11777 either “early” in infection (using a 14 day course, starting 1 day after infection with the parasite) or “late” in the worms' development (using an 8 day treatment course starting 30 days after infection). The outcomes used as measures of success of treatment with K11777 included the number of worms recovered from mice after euthanasia, the number of worm eggs counted in the liver; the extent of the damage to the liver; and finally, the researchers also looked at activity levels of cysteine proteases in the worms themselves, in particular, those proteases associated with the parasite gut. The results of the early-treatment experiment showed a substantial decrease in worm numbers and egg production. In five of the seven mice treated, eggs were eliminated entirely. Also, there was little measurable liver damage. For the late-treatment experiment, decreased burdens of worms and eggs in the livers of K11777 treated mice were also found, and there was less damage to the livers. Those worms surviving treatment and removed from mice also had much less activity of gut cysteine proteases suggesting that K11777 exerts its effects by targeting worm cysteine proteases. These experiments show that K11777 is a potent antischistosomal agent in mice. It might therefore be a good ‘candidate' molecule for developing future treatments for human schistosomiasis. However, before that stage can be reached, it would be important to carry out clinical trials to test whether K11777 is both safe and effective in schistosomiasis patients. Full details as to which worm cysteine protease(s) is the critical target of K11777 would also need to be worked out, and more information would be needed as to whether the dosing plan used in this study (twice-daily injections for a week to 14 days) can be decreased. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040014. World Health Organization pages about schistosomiasis including links to details on further research into the disease Information from the US Centers for Disease Control for patients and health professionals about schistosomiasis Wikipedia pages on schistosomiasis (Wikipedia is an internet encyclopedia anyone can edit) PLoS Neglected Tropical Diseases is a new journal from the Public Library of Science that is devoted to publishing research on the world's most neglected tropical diseases, including schistosomiasis
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影响因子：
1.5
作者：
MEIRELLES, MNL;JULIANO, L;SCHARFSTEIN, J
通讯作者：
SCHARFSTEIN, J
影响因子：
--
作者：
Greenbaum, D;Medzihradszky, KF;Bogyo, M
通讯作者：
Bogyo, M
影响因子：
1.5
作者：
DRESDEN, MH;PAYNE, DC;BASCH, PF
通讯作者：
BASCH, PF
DOI：
10.1084/jem.188.4.725
发表时间：
1998-08-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Engel JC;Doyle PS;Hsieh I;McKerrow JH
通讯作者：
McKerrow JH
影响因子：
3.5
作者：
McKerrow, JH;Engel, JC;Caffrey, CR
通讯作者：
Caffrey, CR