Model-informed drug repurposing: Viral kinetic modelling to prioritize rational drug combinations for COVID-19.
Model-informed drug repurposing: Viral kinetic modelling to prioritize rational drug combinations for COVID-19.
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DOI：
10.1111/bcp.14486
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发表时间：
2021-09
影响因子：
3.4
通讯作者：
Rayner CR
中科院分区：
文献类型：
--
作者：
Dodds MG;Krishna R;Goncalves A;Rayner CR
我们假设病毒动力学模型可能有助于优先考虑COVID-19的合理药物组合。这项研究的目的是使用SARS-CoV-2的病毒细胞周期模型来探索在病毒生命周期的不同阶段起作用的药物或药物组合可能对COVID-19疾病早期阶段相关的感染结果的各种指标产生的潜在影响。使用已用于表征COVID-19患者病毒载量动态的靶细胞限制模型结构，我们进行了模拟，以了解靶向特定速率常数的治疗组合。终点和指标包括病毒载量曲线下面积（AUC）、病毒脱落持续时间和上皮细胞感染。基于SARS-CoV-2生命周期的已知动力学，我们对涉及重新利用的低效力药物的潜在靶向方法进行了排序。我们的模拟表明，靶向受感染宿主细胞内病毒复制或从这些细胞释放的多个中心点是减少病毒载量和宿主细胞感染的可行策略。此外，我们观察到，治疗干预影响病毒脱落持续时间的时间窗机会超过了对保护上皮细胞免受感染的影响或对病毒载量AUC的影响。此外，对减少脱落持续时间的影响可能在表现出延长脱落表型的患者中进一步延长。我们的工作重点是使用基于模型的药物再利用方法，以更好地合理化COVID-19的有效治疗。
We hypothesized that viral kinetic modelling could be helpful to prioritize rational drug combinations for COVID‐19. The aim of this research was to use a viral cell cycle model of SARS‐CoV‐2 to explore the potential impact drugs, or combinations of drugs, that act at different stages in the viral life cycle might have on various metrics of infection outcome relevant in the early stages of COVID‐19 disease. Using a target‐cell limited model structure that has been used to characterize viral load dynamics from COVID‐19 patients, we performed simulations to inform on the combinations of therapeutics targeting specific rate constants. The endpoints and metrics included viral load area under the curve (AUC), duration of viral shedding and epithelial cells infected. Based on the known kinetics of the SARS‐CoV‐2 life cycle, we rank ordered potential targeted approaches involving repurposed, low‐potency agents. Our simulations suggest that targeting multiple points central to viral replication within infected host cells or release from those cells is a viable strategy for reducing both viral load and host cell infection. In addition, we observed that the time‐window opportunity for a therapeutic intervention to effect duration of viral shedding exceeds the effect on sparing epithelial cells from infection or impact on viral load AUC. Furthermore, the impact on reduction on duration of shedding may extend further in patients who exhibit a prolonged shedder phenotype. Our work highlights the use of model‐informed drug repurposing approaches to better rationalize effective treatments for COVID‐19.
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