Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.
Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.
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兽医苯唑替洛尔斯是肽酶激活的前药。
DOI：
10.1371/journal.ppat.1008932
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发表时间：
2020-11
期刊：
影响因子：
6.7
通讯作者：
Barrett MP
中科院分区：
文献类型：
--
作者：
Giordani F;Paape D;Vincent IM;Pountain AW;Fernández-Cortés F;Rico E;Zhang N;Morrison LJ;Freund Y;Witty MJ;Peter R;Edwards DY;Wilkes JM;van der Hooft JJJ;Regnault C;Read KD;Horn D;Field MC;Barrett MP
刚果锥虫（Trypanosoma congolense）、刚果锥虫（T.间日疟原虫和T.每年造成数十亿美元的粮食生产损失。迫切需要新的治疗方法。令人鼓舞的是，有前途的抗锥虫苯并氧杂硼杂环戊烯正在兽医学开发中。在这里，我们表明，这些化合物的最有效的子类是锥虫丝氨酸羧肽酶（CBPs）激活的前药。T.布氏杆菌，由于含有CBP基因的三个串联拷贝的基因座内的部分缺失。T.刚果寄生虫，拥有一个更大的阵列相关的CBP，也发展了耐药性AN 11736通过基因座内的缺失。在T.布氏杆菌证实CBP功能丧失是抗性的主要机制，CRISPR-Cas9编辑证明基因座内的部分缺失足以赋予抗性。CBP在T. brucei或T.刚果人AN 11736抗性系恢复了药物敏感性。CBP通过将苯并氧杂硼杂环戊烯AN 11736裂解为羧酸衍生物而起作用，揭示了前药活化机制。CBP活性的丧失导致AN 11736的净摄取大量减少，表明前药代谢产生的浓度梯度促进了进入。AN 11736是苯并氧杂硼杂环戊烯类的成员，被确定为动物非洲锥虫病的发展候选者，这是一种具有巨大经济影响的致命牲畜疾病。作为其早期评估阶段的一部分，我们着手揭示这种新的锥虫杀虫剂的风险和耐药性模式。我们发现AN 11736的行为就像一种前药，一旦进入锥虫体内，就会被特定的丝氨酸羧肽酶的活性切割。AN 11736抗性布氏锥虫和T. congolense在丝氨酸羧肽酶基因阵列中有缺失，导致它们不能有效地加工母体药物。具有类似子结构的其他苯并氧杂硼杂环戊烯也是丝氨酸羧肽酶的底物，因此我们的研究结果在考虑这类化合物的未来开发和部署方面具有重要意义。
Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T. brucei, due to partial deletion within the locus containing three tandem copies of the CBP genes. T. congolense parasites, which possess a larger array of related CBPs, also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T. brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T. brucei or T. congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism. AN11736 is a member of the benzoxaborole class identified as a development candidate for animal African trypanosomiasis, a deadly livestock disease with huge economic impact. As part of its early evaluation phase, we set to unravel the risk and mode of resistance to this new trypanocide. We discovered that AN11736 behaves as a prodrug that, once inside trypanosomes, is cleaved by the activity of specific serine carboxypeptidases. AN11736-resistant Trypanosoma brucei and T. congolense had deletions within the serine carboxypeptidase gene array, resulting in their being unable to efficiently process the parent drug. Other benzoxaboroles with a similar sub-structure are also substrates for the serine carboxypeptidases, hence our findings assume great importance in considering the future development and deployment of this class of compounds.
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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
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Liang H
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48
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发现新型基于苯并恶硼罗的有效抗锥虫药物。
影响因子：
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作者：
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通讯作者：
Plattner, Jacob J.
影响因子：
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作者：
ENDRIZZI, JA;BREDDAM, K;REMINGTON, SJ
通讯作者：
REMINGTON, SJ
影响因子：
3.8
作者：
Barrett, Michael P.
通讯作者：
Barrett, Michael P.