期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 14, 期 6, 页码 757-765出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.3c00051
关键词
Frameshifting; SARS-CoV-2; RNA; small-moleculemicroarrays
In this study, small molecules that target the frameshifting element (FSE) in the SARS-CoV-2 RNA genome were discovered and characterized using high-throughput small-molecule microarray (SMM) screening. These compounds showed mid-micromolar binding affinity to the FSE RNA and had a binding mode distinct from previously reported FSE binders. Furthermore, these compounds were active in in vitro and in-cell dual-fluorescent-reporter frameshifting assays, indicating the potential of targeting RNA structural elements with druglike compounds to alter viral protein expression.
Targeting structured RNA elements in the SARS-CoV-2 viralgenomewith small molecules is an attractive strategy for pharmacologicalcontrol over viral replication. In this work, we report the discoveryof small molecules that target the frameshifting element (FSE) inthe SARS-CoV-2 RNA genome using high-throughput small-molecule microarray(SMM) screening. A new class of aminoquinazoline ligands for the SARS-CoV-2FSE are synthesized and characterized using multiple orthogonal biophysicalassays and structure-activity relationship (SAR) studies. Thiswork reveals compounds with mid-micromolar binding affinity (K (D) = 60 +/- 6 mu M) to the FSE RNA andsupports a binding mode distinct from previously reported FSE bindersMTDB and merafloxacin. In addition, compounds are active in in vitro dual-luciferase and in-cell dual-fluorescent-reporterframeshifting assays, highlighting the promise of targeting structuredelements of RNAs with druglike compounds to alter expression of viralproteins.
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