Laboratório de Virologia Molecular e Biotecnologia Marinha, Programa de Pós-graduação em Ciências e Biotecnologia, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, Brazil.
Gerência de Desenvolvimento Tecnológico, Instituto Vital Brazil, Niterói, RJ, 24230-410, Brazil.
Arch Microbiol. 2024 Sep 18;206(10):406. doi: 10.1007/s00203-024-04135-9.
Mayaro virus (MAYV) is the causative agent of Mayaro fever, which is characterized mainly by acute fever and long-term severe arthralgia, common manifestations of other arbovirus infections, making the correct diagnosis a challenge. Besides, MAYV infections have been reported in South America, especially in Brazil. However, the lack of vaccines or specific antiviral drugs to control these infections makes the search for new antivirals an urgent need. Herein, we evaluated the antiviral potential of synthetic β-enaminoesters derivatives against MAYV replication and their pharmacokinetic and toxicological (ADMET) properties using in vitro and in silico strategies. For this purpose, Vero cells were infected with MAYV at an MOI of 0.1, treated with compounds (50 µM) for 24 h, and virus titers were quantified by plaque reduction assays. Compounds 2b (83.33%) and 2d (77.53%) exhibited the highest activity with inhibition rates of 83.33% and 77.53%, respectively. The most active compounds 2b (EC = 18.92 µM; SI > 52.85), and 2d (EC = 14.52 µM; SI > 68.87) exhibited higher potency and selectivity than the control drug suramin (EC = 38.97 µM; SI > 25.66). Then, we investigated the mechanism of action of the most active compounds. None of the compounds showed virucidal activity, neither inhibited virus adsorption, but compound 2b inhibited virus entry (62.64%). Also, compounds 2b and 2d inhibited some processes involved with the release of new virus particles. Finally, in silico results indicated good ADMET parameters of the most active compounds and reinforced their promising profile as drug candidates against MAYV.
马亚罗病毒（MAYV）是马亚罗热的病原体，其特征主要为急性发热和长期严重的关节痛，这些都是其他虫媒病毒感染的常见表现，使得正确诊断具有挑战性。此外，MAYV 感染已在南美洲报告，特别是在巴西。然而，缺乏疫苗或控制这些感染的特定抗病毒药物使得寻找新的抗病毒药物成为当务之急。在此，我们使用体外和计算策略评估了合成 β-烯胺酯衍生物对 MAYV 复制的抗病毒潜力及其药代动力学和毒理学（ADMET）特性。为此，用 MAYV 在 MOI 为 0.1 感染 Vero 细胞，用化合物（50 μM）处理 24 h，并用噬斑减少法测定病毒滴度。化合物 2b（83.33%）和 2d（77.53%）表现出最高的活性，抑制率分别为 83.33%和 77.53%。最有效的化合物 2b（EC=18.92 μM；SI>52.85）和 2d（EC=14.52 μM；SI>68.87）比对照药物苏拉明（EC=38.97 μM；SI>25.66）具有更高的效力和选择性。然后，我们研究了最有效化合物的作用机制。这些化合物均没有显示出病毒杀灭活性，既不抑制病毒吸附，也不抑制病毒进入，但化合物 2b 抑制病毒进入（62.64%）。此外，化合物 2b 和 2d 抑制了一些与新病毒颗粒释放有关的过程。最后，计算结果表明最有效化合物具有良好的 ADMET 参数，并增强了它们作为 MAYV 候选药物的有前途的特征。
