Acridones as promising drug candidates against Oropouche virus

Oropouche virus (OROV) is an emerging vector-borne arbovirus found in South America that causes Oropouche fever, a febrile infection similar to dengue fever. It has a high epidemic potential, causing illness in over 500,000 cases diagnosed since the virus was first discovered in 1955. Currently, the prevention of human viral infection depends on vaccination, but availability for many viruses is limited, and they are classified as neglected viruses. At present, there are no vaccines or antiviral treatments available. An alternative approach to limiting the spread of the virus is to selectively disrupt viral replication mechanisms. Here, we demonstrate the inhibitory effect of acridones, which efficiently inhibited viral replication by 99.9 % in vitro. To evaluate possible mechanisms of action, we conducted tests with dsRNA, an intermediate in virus replication, as well as MD simulations, docking, and binding free energy analysis. The results showed a strong interaction between FAC21 and the OROV endonuclease, which possibly limits the interaction of viral RNA with other proteins. Therefore, our results suggest a dual mechanism of antiviral action, possibly caused by ds-RNA intercalation. In summary, our findings demonstrate that a new generation of antiviral drugs could be developed based on the selective optimization of molecules.

奥罗普切病毒（Oropouche virus, OROV）是一种新近出现的媒介传播型虫媒病毒（arbovirus），主要分布于南美洲，可引发奥罗普切热——一种与登革热相似的发热性感染疾病。该病毒具备极高的流行潜力，自1955年首次被发现以来，已累计造成超50万例确诊感染病例。当前，人类病毒性感染的预防手段主要依赖疫苗接种，但多数病毒的疫苗供应十分有限，这类病毒也被归类为被忽视病毒（neglected viruses）。目前，针对奥罗普切病毒既无获批疫苗，也无特效抗病毒治疗手段。而抑制病毒传播的另一可行策略，是选择性阻断病毒的复制机制。本研究中，我们验证了吖啶酮类化合物（acridones）的抗病毒活性：该类化合物在体外实验中可高效抑制病毒复制，抑制率达99.9%。为探究其潜在作用机制，我们以病毒复制过程中的中间产物双链RNA（double-stranded RNA, dsRNA）为对象开展实验，并结合分子动力学（molecular dynamics, MD）模拟、分子对接以及结合自由能分析等手段进行研究。实验结果显示，FAC21与奥罗普切病毒核酸内切酶（endonuclease）之间存在强相互作用，这可能会阻断病毒RNA与其他宿主蛋白的结合。据此，我们的研究结果提示该化合物具备双重抗病毒作用机制，其可能通过双链RNA嵌入发挥效用。综上，本研究结果表明，可通过对分子进行选择性优化，开发出新一代抗奥罗普切病毒药物。