Repurposing Carvedilol as a Novel Inhibitor of the Trypanosoma cruzi Autophagy Flux That Affects Parasite Replication and Survival.
Repurposing Carvedilol as a Novel Inhibitor of the Trypanosoma cruzi Autophagy Flux That Affects Parasite Replication and Survival.
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DOI：
10.3389/fcimb.2021.657257
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发表时间：
2021
影响因子：
5.7
通讯作者：
Romano PS
中科院分区：
文献类型：
--
作者：
Rivero CV;Martínez SJ;Novick P;Cueto JA;Salassa BN;Vanrell MC;Li X;Labriola CA;Polo LM;Engman DM;Clos J;Romano PS
T.克氏锥虫病的病原体克氏锥虫是一种寄生虫，能够感染不同类型的宿主细胞，并在人类和动物宿主的组织中长期存在。这些特点以及缺乏有效的治疗慢性阶段的疾病，促成了持久性和蔓延的疾病在世界各地。迫切需要找到治疗恰加斯病的新疗法。药物再利用是为不同疾病寻找新药的一种有前途和节省成本的策略。在这项工作中，我们描述了卡维地洛对T。克鲁兹通过虚拟筛选选择的这种化合物增加了以较低酸度和水解性质为特征的不成熟自噬体的积累。由于这一行动，锥鞭毛体的生存和上鞭毛体和无鞭毛体的复制受损，导致感染和寄生虫负荷显着减少。此外，卡维地洛降低了感染小鼠的全身寄生虫负荷峰值。总之，在这项工作中，我们提出了一个再利用的药物具有显着的体外和体内活性，对T。克鲁兹这些数据以及其他药理学特性使卡维地洛成为治疗恰加斯病的有吸引力的领先药物。
T. cruzi, the causal agent of Chagas disease, is a parasite able to infect different types of host cells and to persist chronically in the tissues of human and animal hosts. These qualities and the lack of an effective treatment for the chronic stage of the disease have contributed to the durability and the spread of the disease around the world. There is an urgent necessity to find new therapies for Chagas disease. Drug repurposing is a promising and cost-saving strategy for finding new drugs for different illnesses. In this work we describe the effect of carvedilol on T. cruzi. This compound, selected by virtual screening, increased the accumulation of immature autophagosomes characterized by lower acidity and hydrolytic properties. As a consequence of this action, the survival of trypomastigotes and the replication of epimastigotes and amastigotes were impaired, resulting in a significant reduction of infection and parasite load. Furthermore, carvedilol reduced the whole-body parasite burden peak in infected mice. In summary, in this work we present a repurposed drug with a significant in vitro and in vivo activity against T. cruzi. These data in addition to other pharmacological properties make carvedilol an attractive lead for Chagas disease treatment.
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影响因子：
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