An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease.
An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease.
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一个综合的方法来确定新的抗丝虫导致治疗河盲症，一种被忽视的热带疾病。
DOI：
10.3390/pathogens10010071
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发表时间：
2021-01-14
期刊：
影响因子：
--
通讯作者：
Mitreva M
中科院分区：
文献类型：
--
作者：
Tyagi R;Bulman CA;Cho-Ngwa F;Fischer C;Marcellino C;Arkin MR;McKerrow JH;McNamara CW;Mahoney M;Tricoche N;Jawahar S;Janetka JW;Lustigman S;Sakanari J;Mitreva M
丝虫给全世界数百万人带来多种使人衰弱的疾病，包括河盲症。目前可用的药物通过杀死幼虫（微丝蚴）来减少传播，但没有针对在宿主体内存活和繁殖很长时间的成虫寄生虫（杀大丝蚴）的有效治疗方法。为了确定有效的杀大丝虫剂，我们对 2121 种已批准临床用于治疗彭亨丝虫成虫的药物库进行了表型筛选，并通过将这些结果与药物和相关靶标的计算优先级相结合，对命中进行进一步研究。结果鉴定出 18 种具有抗大丝虫杀灭活性的化合物，其中两类，唑类和天冬氨酸蛋白酶抑制剂，得到了进一步扩展。跟踪盘尾丝虫筛查。 （成虫盘尾丝虫和前成虫盘尾丝虫）证实了 13 种药物的活性（大多数药物的 IC50 < 10 μM），并且对罗阿微丝蚴子集的反筛选显示，有可能识别出选择性药物，在治疗共感染个体时预防不良事件。还观察到阶段特异性活动。其中许多药物都适合结构优化，并且还具有已知的典型靶点，这使它们成为进一步优化的有希望的候选药物，从而可以识别和表征新型抗巨丝虫药物。
Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult Brugia pahangi and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets. This resulted in the identification of 18 hits with anti-macrofilaricidal activity, of which two classes, azoles and aspartic protease inhibitors, were further expanded upon. Follow up screening against Onchocerca spp. (adult Onchocerca ochengi and pre-adult O. volvulus) confirmed activity for 13 drugs (the majority having IC50 < 10 μM), and a counter screen of a subset against L. loa microfilariae showed the potential to identify selective drugs that prevent adverse events when co-infected individuals are treated. Stage specific activity was also observed. Many of these drugs are amenable to structural optimization, and also have known canonical targets, making them promising candidates for further optimization that can lead to identifying and characterizing novel anti-macrofilarial drugs.
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影响因子：
21.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Choi, Seoung-ryoung;Pradhan, Anupam;Avery, Mitchell A.
通讯作者：
Avery, Mitchell A.
影响因子：
5.7
作者：
Carrillo-Munoz, Alfonso Javier;Tur-Tur, Cristina;Quindos, Guillermo
通讯作者：
Quindos, Guillermo
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：
120.1
作者：
Drag, Marcin;Salvesen, Guy S.
通讯作者：
Salvesen, Guy S.