Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections.
Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections.
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冠状酸吡咯烷A用于短道抗毛 - 丝状感染的大脂情况治疗。
DOI：
10.1371/journal.pntd.0008930
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发表时间：
2020-12
影响因子：
3.8
通讯作者：
Hoerauf A
中科院分区：
文献类型：
--
作者：
Schiefer A;Hübner MP;Krome A;Lämmer C;Ehrens A;Aden T;Koschel M;Neufeld H;Chaverra-Muñoz L;Jansen R;Kehraus S;König GM;Pogorevc D;Müller R;Stadler M;Hüttel S;Hesterkamp T;Wagner K;Pfarr K;Hoerauf A
目前为消除被忽视的热带病盘尾丝虫病和淋巴丝虫病所作的努力，由于缺乏短期的大丝虫病-成虫-杀虫治疗而受到阻碍。盘尾丝虫病和淋巴丝虫病分别由丝虫病线虫、盘尾丝虫病和布鲁贾丝虫病引起。与主要针对微丝虫的伊维菌素或乙基卡马嗪等标准治疗相比，强力霉素等抗沃尔巴克氏菌抗生素针对的是丝虫必需的沃尔巴克氏菌内共生菌，是一种安全的成虫灭菌和大丝虫杀灭方案的原型。然而，强力霉素需要4-5周的治疗方案和禁忌症限制了它的使用。因此，我们测试了临床前抗沃尔巴克氏体候选药物Corallopyronin A （CorA）在初始和慢性丝虫病感染中的体内疗效。感染后立即开始的14天CorA治疗清除了丝虫中90%的沃尔巴克氏体内共生体，并阻止了成虫的发育。以30 mg/kg每天两次（BID）的CorA治疗明显感染微丝沙鼠14天，可使成丝和微丝中的沃尔巴克氏体内共生菌持续减少50%至99%，随后完全抑制丝胚发生，导致微丝被清除。CorA和阿苯达唑的联合治疗在7天后实现了微丝虫清除，其BID较低剂量为10 mg/kg CorA，人体等效剂量为1.4 mg/kg。阿苯达唑是一种目前在大规模给药期间共同给药的药物，以前显示可增强抗沃尔巴克氏体药物的疗效。重要的是，这种组合导致了成虫负担的显著减少，这一点尚未在该模型中测试的其他抗沃尔巴克氏体候选物中发表。综上所述，CorA是丝虫病的临床前候选药物，它显著减少了实现持续沃尔巴克氏体清除、微丝虫病清除和胚胎发生抑制所需的治疗时间。与阿苯达唑联合使用，CorA在治疗7天后具有强大的大丝虫杀灭作用，并满足大丝虫杀灭药物的目标产品配置文件。丝虫病感染可引起被忽视的热带病盘尾丝虫病和淋巴丝虫病。这些疾病的治疗是有限的，因为没有一种耐受性良好的治疗方法可以在短期治疗后杀死成虫。因此，大规模给药（MDA）是用药物暂时清除微丝蚴，即丝蚴的后代，以抑制疾病的传播。由于这些丙二醛治疗多年来每年必须给予1-2次，因此消除盘尾丝虫病和淋巴丝虫病的目标受到阻碍。在目前的研究中，我们研究了一种新的治疗丝虫病的临床前候选药物。Corallopyronin A （CorA）是一种天然化合物，可以清除丝虫病中必需的沃尔巴克氏体内细菌。研究人员利用s形齿毛线虫（Litomosoides sigmodontis）啮齿动物丝虫病模型证明，2周的CorA治疗可清除体内沃尔巴克氏体内共生体，通过抑制丝虫病胚胎发生来维持对微丝虫病的清除。CorA与MDA药物阿苯达唑联合治疗可降低CorA剂量，缩短治疗时间至7天。更重要的是，它还导致了成虫的死亡。针对丝虫病的新药组合（Target Product Profiles）应具有与CorA一样的成虫杀灭效果。
Current efforts to eliminate the neglected tropical diseases onchocerciasis and lymphatic filariasis, caused by the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti or Brugia spp., respectively, are hampered by lack of a short-course macrofilaricidal–adult-worm killing–treatment. Anti-wolbachial antibiotics, e.g. doxycycline, target the essential Wolbachia endosymbionts of filariae and are a safe prototype adult-worm-sterilizing and macrofilaricidal regimen, in contrast to standard treatments with ivermectin or diethylcarbamazine, which mainly target the microfilariae. However, treatment regimens of 4–5 weeks necessary for doxycycline and contraindications limit its use. Therefore, we tested the preclinical anti-Wolbachia drug candidate Corallopyronin A (CorA) for in vivo efficacy during initial and chronic filarial infections in the Litomosoides sigmodontis rodent model. CorA treatment for 14 days beginning immediately after infection cleared >90% of Wolbachia endosymbionts from filariae and prevented development into adult worms. CorA treatment of patently infected microfilaremic gerbils for 14 days with 30 mg/kg twice a day (BID) achieved a sustained reduction of >99% of Wolbachia endosymbionts from adult filariae and microfilariae, followed by complete inhibition of filarial embryogenesis resulting in clearance of microfilariae. Combined treatment of CorA and albendazole, a drug currently co-administered during mass drug administrations and previously shown to enhance efficacy of anti-Wolbachia drugs, achieved microfilarial clearance after 7 days of treatment at a lower BID dose of 10 mg/kg CorA, a Human Equivalent Dose of 1.4 mg/kg. Importantly, this combination led to a significant reduction in the adult worm burden, which has not yet been published with other anti-Wolbachia candidates tested in this model. In summary, CorA is a preclinical candidate for filariasis, which significantly reduces treatment times required to achieve sustained Wolbachia depletion, clearance of microfilariae, and inhibition of embryogenesis. In combination with albendazole, CorA is robustly macrofilaricidal after 7 days of treatment and fulfills the Target Product Profile for a macrofilaricidal drug. Infections with filarial roundworms can cause the disfiguring human neglected tropical diseases onchocerciasis and lymphatic filariasis. Treatment of these diseases is limited, as there is no well-tolerated treatment available that kills the adult worms after a short-term regimen. Thus, mass drug administrations (MDA) are performed with drugs that temporarily clear the microfilariae, the filarial offspring, to inhibit the transmission of the disease. As these MDA treatments have to be given 1–2 times per year for many years, the goal to eliminate onchocerciasis and lymphatic filariasis is hampered. In the present study we investigated a novel preclinical candidate for the treatment of filariasis. Corallopyronin A (CorA) is a natural compound that clears the essential Wolbachia endobacteria of filariae. Using the Litomosoides sigmodontis rodent model of filariasis we demonstrated that 2 weeks of CorA treatment clears Wolbachia endosymbionts in vivo, leading to a maintained clearance of microfilariae by inhibition of filarial embryogenesis. Combination therapy of CorA with the MDA drug albendazole allowed lower CorA doses and shortened treatment to 7 days. More importantly, it also led to the death of the adult filariae. Portfolios (Target Product Profiles) of new drugs against filariae should show adult killing efficacy like CorA.
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影响因子：
158.5
作者：
GREENE, BM;TAYLOR, HR;WILLIAMS, PN
通讯作者：
WILLIAMS, PN
影响因子：
30.8
作者：
Desjardins, Christopher A.;Cerqueira, Gustavo C.;Goldberg, Jonathan M.;Hotopp, Julie C. Dunning;Haas, Brian J.;Zucker, Jeremy;Ribeiro, Jose M. C.;Saif, Sakina;Levin, Joshua Z.;Fan, Lin;Zeng, Qiandong;Russ, Carsten;Wortman, Jennifer R.;Fink, Doran L.;Birren, Bruce W.;Nutman, Thomas B.
通讯作者：
Nutman, Thomas B.
强力霉素会导致在重复的伊维尔梅克蛋白治疗后持续的微毛皮里岛的区域中，在持续的微丝菌中杀死女性OnChocerca volvulus蠕虫的无菌性和增强，这是一项随机，安慰剂对照，双盲试验。
DOI：
10.1093/cid/civ363
发表时间：
2015-08-15
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Debrah AY;Specht S;Klarmann-Schulz U;Batsa L;Mand S;Marfo-Debrekyei Y;Fimmers R;Dubben B;Kwarteng A;Osei-Atweneboana M;Boakye D;Ricchiuto A;Büttner M;Adjei O;Mackenzie CD;Hoerauf A
通讯作者：
Hoerauf A
影响因子：
3.3
作者：
Debrah, Linda Batsa;Phillips, Richard O.;Hoerauf, Achim
通讯作者：
Hoerauf, Achim
影响因子：
3.2
作者：
Erol, Oezlem;Schaeberle, Till F.;Koenig, Gabriele M.
通讯作者：
Koenig, Gabriele M.