Small molecules targeting viral RNA
Small molecules targeting viral RNA
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DOI：
10.1002/wrna.1373
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发表时间：
2016-11-01
影响因子：
7.3
通讯作者：
Hermann, Thomas
中科院分区：
文献类型：
--
作者：
Hermann, Thomas
病毒基因组和转录本中高度保守的非编码 RNA (ncRNA) 元件为扩展抗感染疗法开发的药物靶点提供了新的机会。与 ncRNA 结构结合的配体能够影响相互作用、结构稳定性或构象变化，从而阻断病毒复制所必需的过程。通过小分子抑制剂靶向功能性 RNA 的概念已在多种具有 RNA 基因组的病毒中得到证实。将抗病毒化合物鉴定为 ncRNA 抑制剂的策略越来越强调考虑筛选和配体设计中出现的候选分子的药物样特性。最近针对RNA靶点的抗病毒先导药物发现工作提供了抑制病毒复制的药物样小分子，包括人类免疫缺陷病毒（HIV）、丙型肝炎病毒（HCV）、严重呼吸综合征冠状病毒（SARS CoV）和甲型流感病毒的抑制剂。虽然靶标选择性对于发现有用的 RNA 结合化合物仍然是一个挑战，但人们对定义适合小分子配体抑制的 RNA 靶标的特性有了更好的理解。 HIV、HCV、SARS CoV 和甲型流感中针对病毒 ncRNA 的成功方法的见解将为未来探索 RNA 靶标用于治疗干预其他病毒病原体提供基础，这些病原体产生了紧迫的、未满足的医疗需求。靶向基因组或转录本中的 ncRNA 成分可能有希望的病毒包括昆虫传播的黄病毒（登革热、寨卡病毒和西尼罗河病毒）和丝状病毒（埃博拉病毒和马尔堡病毒）。
Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug-like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug-like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA-binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect-borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg).