Felipe Finger Banfi, Gabriela Camila Krombauer, Amanda Luisa da Fonseca, Renata Rachide Nunes, Silmara Nunes Andrade, Millena Alves de Rezende, Mariana Helena Chaves, Evaldo Dos Santos Monção, Alex Guterres Taranto, Domingos de Jesus Rodrigues, Gerardo Magela Vieira, Whocely Victor de Castro, Fernando de Pilla Varotti, Bruno Antonio Marinho Sanchez
{"title":"从亚马逊蟾蜍Rhinella marina(无尾目:蟾蜍科)中提取的脱氢丁蟾素可作为开发抗疟原虫药物的原型分子。","authors":"Felipe Finger Banfi, Gabriela Camila Krombauer, Amanda Luisa da Fonseca, Renata Rachide Nunes, Silmara Nunes Andrade, Millena Alves de Rezende, Mariana Helena Chaves, Evaldo Dos Santos Monção, Alex Guterres Taranto, Domingos de Jesus Rodrigues, Gerardo Magela Vieira, Whocely Victor de Castro, Fernando de Pilla Varotti, Bruno Antonio Marinho Sanchez","doi":"10.1590/1678-9199-JVATITD-2020-0073","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The resistance against antimalarial drugs represents a global challenge in the fight and control of malaria. The Brazilian biodiversity can be an important tool for research and development of new medicinal products. In this context, toxinology is a multidisciplinary approach on the development of new drugs, including the isolation, purification, and evaluation of the pharmacological activities of natural toxins. The present study aimed to evaluate the cytotoxicity, as well as the antimalarial activity <i>in silico</i> and <i>in vitro</i> of four compounds isolated from <i>Rhinella marina</i> venom as potential oral drug prototypes.</p><p><strong>Methods: </strong>Four compounds were challenged against 35 target proteins from <i>P. falciparum</i> and screened to evaluate their physicochemical properties using docking assay in Brazilian Malaria Molecular Targets (BraMMT) software and <i>in silico</i> assay in OCTOPUS® software. The <i>in vitro</i> antimalarial activity of the compounds against the 3D7 <i>Plasmodium falciparum</i> clones were assessed using the SYBR Green I based assay (IC<sub>50</sub>). For the cytotoxic tests, the LD<sub>50</sub> was determined in human pulmonary fibroblast cell line using the [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay.</p><p><strong>Results: </strong>All compounds presented a ligand-receptor interaction with ten <i>Plasmodium falciparum</i>-related protein targets, as well as antimalarial activity against chloroquine resistant strain (IC<sub>50</sub> = 3.44 μM to 19.11 μM). Three of them (dehydrobufotenine, marinobufagin, and bufalin) showed adequate conditions for oral drug prototypes, with satisfactory prediction of absorption, permeability, and absence of toxicity. In the cell viability assay, only dehydrobufotenin was selective for the parasite.</p><p><strong>Conclusions: </strong>Dehydrobufotenin revealed to be a potential oral drug prototype presenting adequate antimalarial activity and absence of cytotoxicity, therefore should be subjected to further studies.</p>","PeriodicalId":520810,"journal":{"name":"The journal of venomous animals and toxins including tropical diseases","volume":" ","pages":"e20200073"},"PeriodicalIF":0.0000,"publicationDate":"2021-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812938/pdf/","citationCount":"5","resultStr":"{\"title\":\"Dehydrobufotenin extracted from the Amazonian toad <i>Rhinella marina</i> (Anura: Bufonidae) as a prototype molecule for the development of antiplasmodial drugs.\",\"authors\":\"Felipe Finger Banfi, Gabriela Camila Krombauer, Amanda Luisa da Fonseca, Renata Rachide Nunes, Silmara Nunes Andrade, Millena Alves de Rezende, Mariana Helena Chaves, Evaldo Dos Santos Monção, Alex Guterres Taranto, Domingos de Jesus Rodrigues, Gerardo Magela Vieira, Whocely Victor de Castro, Fernando de Pilla Varotti, Bruno Antonio Marinho Sanchez\",\"doi\":\"10.1590/1678-9199-JVATITD-2020-0073\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The resistance against antimalarial drugs represents a global challenge in the fight and control of malaria. The Brazilian biodiversity can be an important tool for research and development of new medicinal products. In this context, toxinology is a multidisciplinary approach on the development of new drugs, including the isolation, purification, and evaluation of the pharmacological activities of natural toxins. The present study aimed to evaluate the cytotoxicity, as well as the antimalarial activity <i>in silico</i> and <i>in vitro</i> of four compounds isolated from <i>Rhinella marina</i> venom as potential oral drug prototypes.</p><p><strong>Methods: </strong>Four compounds were challenged against 35 target proteins from <i>P. falciparum</i> and screened to evaluate their physicochemical properties using docking assay in Brazilian Malaria Molecular Targets (BraMMT) software and <i>in silico</i> assay in OCTOPUS® software. The <i>in vitro</i> antimalarial activity of the compounds against the 3D7 <i>Plasmodium falciparum</i> clones were assessed using the SYBR Green I based assay (IC<sub>50</sub>). For the cytotoxic tests, the LD<sub>50</sub> was determined in human pulmonary fibroblast cell line using the [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay.</p><p><strong>Results: </strong>All compounds presented a ligand-receptor interaction with ten <i>Plasmodium falciparum</i>-related protein targets, as well as antimalarial activity against chloroquine resistant strain (IC<sub>50</sub> = 3.44 μM to 19.11 μM). Three of them (dehydrobufotenine, marinobufagin, and bufalin) showed adequate conditions for oral drug prototypes, with satisfactory prediction of absorption, permeability, and absence of toxicity. 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引用次数: 5
摘要
背景:抗疟药物耐药性是疟疾防治中的一个全球性挑战。巴西的生物多样性可以成为研究和开发新药品的重要工具。在此背景下，毒理学是开发新药的多学科方法，包括天然毒素的分离、纯化和药理活性评价。本研究旨在评价从小犀牛毒液中分离的四种化合物作为潜在的口服药物原型的细胞毒性和体外抗疟活性。方法:采用巴西疟疾分子靶点(BraMMT)软件对接实验和OCTOPUS®软件硅质实验，对4种化合物攻击35种恶性疟原虫靶蛋白进行筛选，评价其理化性质。采用基于SYBR Green I的体外抗疟试验(IC50)评估化合物对3D7恶性疟原虫克隆的体外抗疟活性。在细胞毒性试验中，采用[3(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑](MTT)法测定人肺成纤维细胞系的LD50。结果:所有化合物均与10个恶性疟原虫相关蛋白靶点存在配体-受体相互作用，对氯喹耐药菌株具有抗疟活性(IC50 = 3.44 μM ~ 19.11 μM)。其中三种(脱氢蟾蟾素、马里诺蟾蟾素和蟾蟾灵)具有足够的条件用于口服药物原型，具有令人满意的吸收、渗透性和无毒性预测。在细胞活力测定中，只有脱氢丁氟tenin对寄生虫有选择性。结论:脱氢丁氟tenin是一种潜在的口服药物原型，具有足够的抗疟活性和无细胞毒性，因此应进行进一步的研究。
Dehydrobufotenin extracted from the Amazonian toad Rhinella marina (Anura: Bufonidae) as a prototype molecule for the development of antiplasmodial drugs.
Background: The resistance against antimalarial drugs represents a global challenge in the fight and control of malaria. The Brazilian biodiversity can be an important tool for research and development of new medicinal products. In this context, toxinology is a multidisciplinary approach on the development of new drugs, including the isolation, purification, and evaluation of the pharmacological activities of natural toxins. The present study aimed to evaluate the cytotoxicity, as well as the antimalarial activity in silico and in vitro of four compounds isolated from Rhinella marina venom as potential oral drug prototypes.
Methods: Four compounds were challenged against 35 target proteins from P. falciparum and screened to evaluate their physicochemical properties using docking assay in Brazilian Malaria Molecular Targets (BraMMT) software and in silico assay in OCTOPUS® software. The in vitro antimalarial activity of the compounds against the 3D7 Plasmodium falciparum clones were assessed using the SYBR Green I based assay (IC50). For the cytotoxic tests, the LD50 was determined in human pulmonary fibroblast cell line using the [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay.
Results: All compounds presented a ligand-receptor interaction with ten Plasmodium falciparum-related protein targets, as well as antimalarial activity against chloroquine resistant strain (IC50 = 3.44 μM to 19.11 μM). Three of them (dehydrobufotenine, marinobufagin, and bufalin) showed adequate conditions for oral drug prototypes, with satisfactory prediction of absorption, permeability, and absence of toxicity. In the cell viability assay, only dehydrobufotenin was selective for the parasite.
Conclusions: Dehydrobufotenin revealed to be a potential oral drug prototype presenting adequate antimalarial activity and absence of cytotoxicity, therefore should be subjected to further studies.
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