Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates.
Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates.
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DOI：
10.1038/s41564-022-01211-y
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发表时间：
2022-10
影响因子：
28.3
通讯作者：
中科院分区：
文献类型：
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克氏锥虫（Trypanosoma cruzi）是南美锥虫病的病原体，可能感染数千万人，主要是拉丁美洲的人，造成发病和死亡。治疗和预防南美锥虫病的选择有限，而且利用不足。在这里，我们描述了一系列苯并氧杂硼杂环戊烯化合物的发现与纳摩尔活性对T细胞外和细胞内阶段。克鲁兹利用相关动质体中正在进行的药物发现工作，以及T. cruzi，我们已经鉴定了前药AN 15368，其被寄生虫羧肽酶激活以产生靶向T.克鲁兹发现AN15368在体外和体内对一系列遗传上不同的T. cruzi谱系，并且在具有长期自然获得性感染的非人灵长类动物（NHP）中具有一致的治愈性。在NHP中的治疗也没有发现可检测的急性毒性或长期健康或生殖影响。因此，AN15368是一种经过广泛验证的、明显安全的、临床上准备好的候选药物，具有预防和治疗恰加斯病的潜力。一种新发现的苯并氧杂硼杂环戊烯前药AN15368治疗小鼠和自然感染的非人类灵长类动物的克氏锥虫感染（恰加斯病的原因）。
Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease. A newly discovered benzoxaborole prodrug AN15368 cures Trypanosoma cruzi infection (the cause of Chagas disease) in mice and in naturally infected non-human primates.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
7.3
作者：
Fleau, Charlotte;Padilla, Angel;Courtemanche, Gilles
通讯作者：
Courtemanche, Gilles
影响因子：
2.7
作者：
Akama T;Zhang YK;Freund YR;Berry P;Lee J;Easom EE;Jacobs RT;Plattner JJ;Witty MJ;Peter R;Rowan TG;Gillingwater K;Brun R;Nare B;Mercer L;Xu M;Wang J;Liang H
通讯作者：
Liang H
影响因子：
6.4
作者：
Bustamante, Juan M.;Craft, Julie M.;Tarleton, Rick L.
通讯作者：
Tarleton, Rick L.
影响因子：
5.8
作者：
Bellini V;Swale C;Brenier-Pinchart MP;Pezier T;Georgeault S;Laurent F;Hakimi MA;Bougdour A
通讯作者：
Bougdour A