Abstract：
Infectious pancreatic necrosis virus (IPNV) is an important pathogen that is threatening the worldwide salmon and trout industry. But there is no therapeutic drug available for now. In this study, we demonstrate that MK-0608 is highly efficient against IPNV and low cytotoxic, with a 50 % effective concentration (EC50) of 0.20 μM and selectivity index (SI) of about 268. Time of addition assay illustrated that MK-0608 targeted the early stage of IPNV life cycle. Furthermore, we found that MK-0608 blocked IPNV attachment on the premise of sufficient pre-incubation time but MK-0608 did not influence viral internalization and release. MK-0608 could inhibit IPNV genome synthesis, and combination with ribavirin enhanced the inhibition effect, which might be functional via binding to IPNV RNA dependent RNA polymerase (RdRp), which was predicted by using molecular docking methods. In vivo test showed that IPNV was extremely suppressed in the rainbow trout (Oncorhynchus mykiss) with one single dose of MK-0608, and the higher dosage of 50 mg/kg could cause 3 log decrease of IPNV loads in fish tissues.
摘要：
传染性胰腺坏死病毒（IPNV）是威胁全球鲑鱼和鳟鱼产业的重要病原体。但是目前还没有治疗药物。在这项研究中,我们证明了MK-0608对IPNV高效且细胞毒性低，具有0.20μM的50%有效浓度(EC50)和约268的选择性指数(SI)。添加时间测定说明MK-0608靶向IPNV生命周期的早期阶段。此外，我们发现MK-0608在足够的预孵育时间的前提下阻断IPNV附着，但MK-0608不影响病毒内化和释放。MK-0608可以抑制IPNV基因组合成，与利巴韦林联合使用增强了抑制作用，可能通过与IPNVRNA依赖性RNA聚合酶（RdRp）结合而起作用，这是用分子对接方法预测的。体内试验表明，单剂量MK-0608可极大地抑制虹鳟鱼（Oncorhynchusmykiss）中的IPNV，较高的剂量50mg/kg可导致鱼组织中IPNV负荷减少3个对数。
