Targeted protein degradation as an antiviral approach.
Targeted protein degradation as an antiviral approach.
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DOI：
10.1016/j.antiviral.2022.105480
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发表时间：
2022-12
影响因子：
7.6
通讯作者：
A. Chakravarty;Priscilla L. Yang
中科院分区：
文献类型：
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作者：
A. Chakravarty;Priscilla L. Yang
靶向蛋白质降解（TPD）已成为药物发现的新模式。在这种方法中，小分子用于驱动目标靶蛋白的降解。大多数直接作用抗病毒药物 (DAA) 会抑制或扰乱其病毒蛋白靶标的活性，并具有占据驱动的药理学，而具有基于 TPD 机制的小分子则通过诱导靶标降解的能力发挥事件驱动的药理学作用。这些对比机制可能导致药物功效和药效学的显着差异，这可能有助于开发新型抗病毒药物。虽然 TPD 目前在癌症生物学和自身免疫性疾病领域得到广泛研究，但尚未作为一种抗病毒策略得到广泛应用。在这里，我们简要回顾了 TPD 药理学以及可用于开发通过 TPD 机制实现抗病毒活性的小分子的工具的现状。我们还强调了 TPD 的一些方面，这些方面可能在抗病毒药物的开发中特别有用，并且我们希望这将激励抗病毒药物研究界对基于 TPD 的抗病毒药物的追求。
Targeted protein degradation (TPD) has emerged as a new modality in drug discovery. In this approach, small molecules are used to drive degradation of the target protein of interest. Whereas most direct-acting antivirals (DAAs) inhibit or derange the activity of their viral protein targets and have occupancy-driven pharmacology, small molecules with a TPD-based mechanism have event-driven pharmacology exerted through their ability to induce target degradation. These contrasting mechanisms can result in significant differences in drug efficacy and pharmacodynamics that may be useful in the development of new classes of antivirals. While now being widely pursued in cancer biology and autoimmune disease, TPD has not yet been widely applied as an antiviral strategy. Here, we briefly review TPD pharmacology along with the current status of tools available for developing small molecules that achieve antiviral activity through a TPD mechanism. We also highlight aspects of TPD that may be especially useful in the development of antivirals and that we hope will motivate pursuit of TPD-based antivirals by the antivirals research community.