Elucidating the molecular mechanisms of small-molecule disruption of viral replication machinery

5.阐明小分子干扰病毒复制的分子机制 机械 项目负责人：胡安·紫苏(CBC) 计算建模和模拟提供了一个强大的工具集来确定原子性 生物过程的潜在机制，如在生物生命周期中发生的机制 病原体。同样，计算方法也可以被用来揭示 这些过程会被小分子疗法改变或破坏。建议的工作 本文旨在阐明小分子的化学和物理效应。 复制机制对一种高度相关的人类病原体，即艾滋病毒-1至关重要。 尽管几种抗逆转录病毒药物取得了成功，但该病毒已经对所有已知的药物产生了抗药性。 值得注意的是，还没有开发出一种药物来对抗病毒这样的大蛋白组合。 因此，衣壳蛋白提供了一个未被开发的治疗靶点。这里提出的工作旨在 阐明小分子对衣壳相关复制的化学和物理影响 对艾滋病毒来说必不可少的机械设备。重要的是，拟议的工作不仅与艾滋病毒患者有关 因为艾滋病毒是其他人类疾病的模型，包括与病毒相关的癌症。此外, 这里开发的尖端方法将直接适用于其他病毒和细菌 装配。

5. Elucidating the molecular mechanisms of small-molecule disruption of viral replication machinery Project Leader: Juan Perilla (CBC) Computational modeling and simulations provide a powerful toolset to determine the atomistic mechanisms underlying biological processes, such as those that occur during the life cycle of a pathogen. Likewise, computational methods can be leveraged to reveal the mechanisms by which these processes are altered or disrupted by small-molecule therapeutics. The work proposed here aims to elucidate the chemical and physical effects of small molecules on the replication machinery essential to a highly relevant human pathogen, namely HIV-1. Despite the success of several antiretrovirals, the virus has evolved resistance to all known drugs. Remarkably, not a single drug has been developed against large protein assemblies like the viral capsid therefore providing an unexploited therapeutic target. The work proposed here aims to elucidate the chemical and physical effects of small molecules on the capsid-related replication machinery essential to HIV. Importantly, the proposed work is not only relevant for HIV patients as HIV serves as a model for other human diseases, including virus-related cancer. In addition, the cutting-edge methods developed herein will be directly applicable to other virus and bacterial assemblies.