Abstract：
BACKGROUND: The new coronavirus (SARS-CoV-2) pandemic emerged in 2019 causing millions of deaths. Vaccines were quickly developed and made available in 2021. Despite the availability of vaccines, some subjects refuse to take the immunizing or present comorbities, therefore developing serious cases of COVID-19, which makes necessary the development of antiviral drugs. Previous studies have demonstrated that ebselen, a selenium-containing molecule, can inhibit SARS-CoV-2 Mpro. In addition, selenium is a trace element that has antiviral and anti-inflammatory properties. Zidovudine (AZT) has been widely used against HIV infections and its action against SARS-CoV-2 may be altered by the structural modification with organochalcogen moieties, but this hypothesis still needs to be tested.
METHODS: In the present work we evaluated the Mpro inhibition capacity (in silico), the safety and antioxidant effect of six organochalcogen AZT-derivatives using the free-living nematode Caenorhabditis elegans, through acute (30 min) and chronic (48) exposure protocols.
RESULTS: We observed that the molecules were safe at a concentration range of 1-500 µM and did not alter any toxicological endpoint evaluated. Furthermore, the molecules are capable to decrease the ROS formation stimulated by hydrogen peroxide, to modulate the expression of important antioxidant enzymes such superoxide-dismutase-3 and glutathione S-transferese-4 and to stimulate the translocation of the DAF-16 to the cell nucleus. In addition, the molecules did not deplete thiol groups, which reinforces their safety and contribution to oxidative stress resistance.
CONCLUSIONS: We have found that compounds S116l (a Tellurium AZT-derivative) and S116h (a Selenium-AZT derivative) presented more promising effects both in silico and in vivo, being strong candidates for further in vivo studies.
METHODS: In the present work we evaluated the Mpro inhibition capacity (in silico), the safety and antioxidant effect of six organochalcogen AZT-derivatives using the free-living nematode Caenorhabditis elegans, through acute (30 min) and chronic (48) exposure protocols.
RESULTS: We observed that the molecules were safe at a concentration range of 1-500 µM and did not alter any toxicological endpoint evaluated. Furthermore, the molecules are capable to decrease the ROS formation stimulated by hydrogen peroxide, to modulate the expression of important antioxidant enzymes such superoxide-dismutase-3 and glutathione S-transferese-4 and to stimulate the translocation of the DAF-16 to the cell nucleus. In addition, the molecules did not deplete thiol groups, which reinforces their safety and contribution to oxidative stress resistance.
CONCLUSIONS: We have found that compounds S116l (a Tellurium AZT-derivative) and S116h (a Selenium-AZT derivative) presented more promising effects both in silico and in vivo, being strong candidates for further in vivo studies.
摘要：
背景：2019年出现了新的冠状病毒（SARS-CoV-2）大流行，造成数百万人死亡。疫苗迅速开发并在2021年提供。尽管有疫苗，一些受试者拒绝接种疫苗或出现合并症，因此发展出严重的COVID-19病例，这使得抗病毒药物的开发成为必要。以前的研究表明，埃布硒，一种含硒的分子,能抑制SARS-CoV-2Mpro。此外,硒是一种微量元素，具有抗病毒和抗炎特性。齐多夫定（AZT）已广泛用于抗HIV感染，其对SARS-CoV-2的作用可能通过有机硫属元素部分的结构修饰而改变，但是这个假设仍然需要检验。
方法：在目前的工作中，我们评估了Mpro抑制能力（计算机模拟），使用自由生活线虫秀丽隐杆线虫的六种有机硫属元素AZT衍生物的安全性和抗氧化作用，通过急性（30分钟）和慢性（48）暴露方案。
结果：我们观察到分子在1-500µM的浓度范围内是安全的，并且没有改变评估的任何毒理学终点。此外，这些分子能够减少过氧化氢刺激的ROS形成，调节重要的抗氧化酶的表达，例如超氧化物歧化酶3和谷胱甘肽S-transperese-4，并刺激DAF-16向细胞核的易位。此外,分子没有耗尽硫醇基团，这加强了它们的安全性和对氧化应激抗性的贡献。
结论：我们发现，化合物S116l（碲AZT衍生物）和S116h（硒-AZT衍生物）在计算机和体内表现出更有希望的效果，是进一步体内研究的有力候选人。
方法：在目前的工作中，我们评估了Mpro抑制能力（计算机模拟），使用自由生活线虫秀丽隐杆线虫的六种有机硫属元素AZT衍生物的安全性和抗氧化作用，通过急性（30分钟）和慢性（48）暴露方案。
结果：我们观察到分子在1-500µM的浓度范围内是安全的，并且没有改变评估的任何毒理学终点。此外，这些分子能够减少过氧化氢刺激的ROS形成，调节重要的抗氧化酶的表达，例如超氧化物歧化酶3和谷胱甘肽S-transperese-4，并刺激DAF-16向细胞核的易位。此外,分子没有耗尽硫醇基团，这加强了它们的安全性和对氧化应激抗性的贡献。
结论：我们发现，化合物S116l（碲AZT衍生物）和S116h（硒-AZT衍生物）在计算机和体内表现出更有希望的效果，是进一步体内研究的有力候选人。
