Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro.
Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro.
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DOI：
10.3390/molecules26092607
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发表时间：
2021-04-29
期刊：
影响因子：
--
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Gao Y;Cao J;Xing P;Altmeyer R;Zhang Y
呼吸道合胞病毒（Respiratory syncytial virus，RSV）是引起婴幼儿、老年人和免疫功能低下者严重下呼吸道感染的主要病原体。目前没有批准的特定药物或疫苗可用于治疗这种病原体。最近，正在研究几种有希望的靶向RSV进入和增殖步骤的候选物。但长期治疗也有可能导致耐药。治疗组合构成了预防耐药性和减少抗病毒剂量的替代方案。因此，我们测试了融合抑制剂（GS 5806、Ziresovir和BMS 433771）和RNA依赖性RNA聚合酶复合物（RdRp）抑制剂（ALS 8176、RSV 604和环巴胺）的体外两种药物组合。统计程序MacSynergy II用于确定药物之间的协同作用、相加作用或拮抗作用。从结果中，我们发现ALS 8176和Ziresovir或GS 5806的组合在体外表现出抗RSV的累加效应，在95%置信区间时相互作用体积分别为50 µM2%和31 µM2%。另一方面，融合抑制剂之间的所有组合在体外均显示出对RSV的拮抗作用，在95%置信区间下，拮抗体积范围为−50 µ M2%至−176 µ M2%。总的来说，我们的结果表明，可以考虑在体外对抗RSV的潜在治疗组合用于进一步的动物和临床评价。
Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from −50 µM2 % to −176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.
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