Targeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders.
Targeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders.
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DOI：
10.1021/acscentsci.0c00984
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发表时间：
2020-10-28
影响因子：
18.2
通讯作者：
Disney MD
中科院分区：
文献类型：
--
作者：
Haniff HS;Tong Y;Liu X;Chen JL;Suresh BM;Andrews RJ;Peterson JM;O'Leary CA;Benhamou RI;Moss WN;Disney MD
COVID-19是一种全球性大流行病，因此需要多种策略来开发对抗它的模式。在此，我们设计了多种生物活性小分子，靶向SARS-CoV-2 RNA基因组中的功能结构，COVID-19的病原体。对RNA基因组结构的分析提供了SARS-CoV-2移码元件的修订模型，特别是其衰减发夹。通过研究RNA聚焦的小分子集合，我们鉴定了一种药物样小分子（C5），其以11 nM的Kd与修改的衰减子发夹结构紧密结合。该化合物稳定发夹的折叠状态，并削弱细胞中的移码。该配体被进一步加工成核糖核酸酶靶向嵌合体（RIBOTAC），以招募细胞核糖核酸酶来破坏病毒基因组（C5-RIBOTAC），并加工成共价分子（C5-Chem-CLIP），该分子验证了直接靶向接合并证明了其对病毒的特异性与高表达的宿主mRNA相比，RNA。RIBOTAC先导优化策略将化合物的生物活性提高了至少10倍。总的来说，这些研究表明SARS-CoV-2 RNA基因组应该被认为是可药用的。COVID-19是由SARS-CoV-2病毒引起的全球大流行病，该病毒具有RNA基因组。我们设计了一些小分子，这些小分子可以结合或降解病毒中的结构化功能元件，以抑制病毒繁殖所必需的过程。
COVID-19 is a global pandemic, thus requiring multiple strategies to develop modalities against it. Herein, we designed multiple bioactive small molecules that target a functional structure within the SARS-CoV-2’s RNA genome, the causative agent of COVID-19. An analysis to characterize the structure of the RNA genome provided a revised model of the SARS-CoV-2 frameshifting element, in particular its attenuator hairpin. By studying an RNA-focused small molecule collection, we identified a drug-like small molecule (C5) that avidly binds to the revised attenuator hairpin structure with a Kd of 11 nM. The compound stabilizes the hairpin’s folded state and impairs frameshifting in cells. The ligand was further elaborated into a ribonuclease targeting chimera (RIBOTAC) to recruit a cellular ribonuclease to destroy the viral genome (C5-RIBOTAC) and into a covalent molecule (C5-Chem-CLIP) that validated direct target engagement and demonstrated its specificity for the viral RNA, as compared to highly expressed host mRNAs. The RIBOTAC lead optimization strategy improved the bioactivity of the compound at least 10-fold. Collectively, these studies demonstrate that the SARS-CoV-2 RNA genome should be considered druggable. COVID-19 is a global pandemic caused by the SARS-CoV-2 virus, which has an RNA genome. We designed small molecules that bind or degrade a structured, functional element in the virus to inhibit a process essential for viral propagation.
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