Haniff Hafeez S, Tong Yuquan, Liu Xiaohui, Chen Jonathan L, Suresh Blessy M, Andrews Ryan J, Peterson Jake M, O'Leary Collin A, Benhamou Raphael I, Moss Walter N, Disney Matthew D
The Scripps Research Institute, Department of Chemistry, Jupiter, Florida 33458, United States.
Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, Iowa 50011, United States.
ACS Cent Sci. 2020 Oct 28;6(10):1713-1721. doi: 10.1021/acscentsci.0c00984. Epub 2020 Sep 30.
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 () that avidly binds to the revised attenuator hairpin structure with a 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 () and into a covalent molecule () 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.
新冠病毒肺炎（COVID-19）是一种全球大流行疾病，因此需要多种策略来开发对抗它的方法。在此，我们设计了多种生物活性小分子，它们靶向新冠病毒肺炎的病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2）RNA基因组中的一个功能结构。对RNA基因组结构进行表征的分析提供了一个修订后的SARS-CoV-2移码元件模型，特别是其衰减子发夹结构。通过研究一个聚焦于RNA的小分子文库，我们鉴定出一种类药物小分子（），它以11 nM的解离常数 avidly 结合到修订后的衰减子发夹结构上。该化合物稳定了发夹的折叠状态并损害细胞中的移码。该配体进一步被设计成一种靶向核糖核酸酶的嵌合体（RIBOTAC），以募集一种细胞核糖核酸酶来破坏病毒基因组（），并被设计成一种共价分子（），该共价分子验证了直接的靶点结合，并证明了其相对于高表达的宿主mRNA对病毒RNA的特异性。RIBOTAC先导优化策略使该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基因组应被视为可成药的。
