Laboratory of Medicinal and Computational Chemistry (LQMC), Centre for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), São Carlos Institute of Physics (IFSC), University of São Paulo (USP), São Carlos, SP, Brazil.
Nuclei of Bioassays, Biosynthesis and Ecophysiology of Natural Products (NuBBE), Department of Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara, SP, Brazil.
PLoS One. 2022 Oct 3;17(10):e0275002. doi: 10.1371/journal.pone.0275002. eCollection 2022.
Investigating the chemical diversity of natural products from tropical environments is an inspiring approach to developing new drug candidates for neglected tropical diseases (NTDs). In the present study, phenotypic screenings for antiprotozoal activity and a combination of computational and biological approaches enabled the identification and characterization of four cytochalasins, which are fungal metabolites from Brazilian biodiversity sources. Cytochalasins A-D exhibited IC50 values ranging from 2 to 20 μM against intracellular Trypanosoma cruzi and Leishmania infantum amastigotes, values comparable to those of the standard drugs benznidazole and miltefosine for Chagas disease and leishmaniasis, respectively. Furthermore, cytochalasins A-D reduced L. infantum infections by more than 80% in THP-1 cells, most likely due to the inhibition of phagocytosis by interactions with actin. Molecular modelling studies have provided useful insights into the mechanism of action of this class of compounds. Furthermore, cytochalasins A-D showed moderate cytotoxicity against normal cell lines (HFF-1, THP-1, and HepG2) and a good overall profile for oral bioavailability assessed in vitro. The results of this study support the use of natural products from Brazilian biodiversity sources to find potential drug candidates for two of the most important NTDs.
从热带环境中的天然产物中研究化学多样性是开发针对被忽视热带病（NTDs）的新药候选物的一种很有启发性的方法。在本研究中，针对抗原生动物活性的表型筛选以及计算和生物学方法的结合，使我们能够鉴定和表征四种细胞松弛素，它们是来自巴西生物多样性来源的真菌代谢产物。细胞松弛素 A-D 对细胞内 Trypanosoma cruzi 和 Leishmania infantum 无鞭毛体的 IC50 值在 2 到 20 μM 之间，与分别用于恰加斯病和利什曼病的标准药物苯并硝唑和米替福新相当。此外，细胞松弛素 A-D 在 THP-1 细胞中使 L. infantum 感染减少了 80%以上，这很可能是由于与肌动蛋白相互作用抑制了吞噬作用。分子建模研究为这类化合物的作用机制提供了有用的见解。此外，细胞松弛素 A-D 对正常细胞系（HFF-1、THP-1 和 HepG2）表现出中等的细胞毒性，并且在体外评估的口服生物利用度方面具有良好的整体概况。这项研究的结果支持使用巴西生物多样性来源的天然产物来寻找针对两种最重要的 NTDs 的潜在药物候选物。
