Fernández Gabriela A, Castro Eliana F, Rosas Rocío A, Fidalgo Daniela M, Adler Natalia S, Battini Leandro, España de Marco Maria J, Fabiani Matias, Bruno Ana M, Bollini Mariela, Cavallaro Lucia V
Laboratorio de Química Medicinal, Centro de Investigaciones en Bionanociencias (CIBION)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Centro de Investigaciones en Ciencias Veterinarias y Agronómicas, Instituto de Virología e Innovaciones Tecnológicas, Instituto Nacional de Tecnología Agropecuaria, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Front Chem. 2020 Dec 10;8:590235. doi: 10.3389/fchem.2020.590235. eCollection 2020.
Bovine viral diarrhea virus (BVDV) belongs to the genus (). In spite of the availability of vaccines, the virus is still causing substantial financial losses to the livestock industry. In this context, the use of antiviral agents could be an alternative strategy to control and reduce viral infections. The viral RNA-dependent RNA polymerase (RdRp) is essential for the replication of the viral genome and constitutes an attractive target for the identification of antiviral compounds. In a previous work, we have identified potential molecules that dock into an allosteric binding pocket of BVDV RdRp via a structure-based virtual screening approach. One of them, -(2-morpholinoethyl)-2-phenylquinazolin-4-amine [, 50% effective concentration (EC) = 9.7 ± 0.5 μM], was selected to perform different chemical modifications. Among 24 derivatives synthesized, eight of them showed considerable antiviral activity. Molecular modeling of the most active compounds showed that they bind to a pocket located in the fingers and thumb domains in BVDV RdRp, which is different from that identified for other non-nucleoside inhibitors (NNIs) such as thiosemicarbazone (TSC). We selected compound 2-[4-(2-phenylquinazolin-4-yl)piperazin-1-yl]ethanol (; EC = 1.7 ± 0.4 μM) for further analysis. Compound was found to inhibit the replication of TSC-resistant BVDV variants, which carry the N264D mutation in the RdRp. In addition, presented adequate solubility in different media and a high-stability profile in murine and bovine plasma.
牛病毒性腹泻病毒（BVDV）属于（）属。尽管有疫苗可用，但该病毒仍给畜牧业造成巨大经济损失。在此背景下，使用抗病毒药物可能是控制和减少病毒感染的一种替代策略。病毒的RNA依赖性RNA聚合酶（RdRp）对于病毒基因组的复制至关重要，是鉴定抗病毒化合物的一个有吸引力的靶点。在之前的一项工作中，我们通过基于结构的虚拟筛选方法鉴定了一些能够对接至BVDV RdRp变构结合口袋的潜在分子。其中一种，-（2-吗啉代乙基）-2-苯基喹唑啉-4-胺[，50%有效浓度（EC）= 9.7±0.5 μM]，被选来进行不同的化学修饰。在合成的24种衍生物中，有8种显示出相当的抗病毒活性。对活性最高的化合物进行分子建模表明，它们结合在BVDV RdRp的手指和拇指结构域中的一个口袋中，这与其他非核苷抑制剂（NNIs）如硫代氨基脲（TSC）所识别的口袋不同。我们选择化合物2-[4-（2-苯基喹唑啉-4-基）哌嗪-1-基]乙醇（；EC = 1.7±0.4 μM）进行进一步分析。发现化合物能抑制携带RdRp中N264D突变的TSC抗性BVDV变体的复制。此外，在不同介质中具有足够的溶解度，并且在小鼠和牛血浆中具有高稳定性。
