Discovery of a self-assembling small molecule that sequesters RNA-binding proteins

• Published in: Chinese chemical letters p. 110135
• Main Authors: Kim, Hyoseok, Cui, Changyi, Toh, Kohei, Ado, Genyir, Ogawa, Tetsuya, Zhang, Yixin, Sato, Shin-ichi, Lim, Yong-Beom, Kurata, Hiroki, Zhou, Lu, Uesugi, Motonari
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.06.2024
• Subjects: Chemical biology; Chemical library; RNA-binding proteins; Small molecule; Translation; Chemical biology; Translation; RNA-binding proteins; Small molecule; Chemical library
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2024.110135

Biomolecular condensates, also known as membraneless organelles, play a crucial role in cellular organization by concentrating or sequestering biomolecules. Despite their importance, synthetically mimicking these organelles using non-peptidic small organic molecules has posed a significant challenge. The present study reports the discovery of D008, a self-assembling small molecule that sequesters a unique subset of RNA-binding proteins. Analysis and screening of a comprehensive collection of approximately 1 million compounds in the Chinese National Compound Library (Shanghai) identified 44 self-assembling small molecules in aqueous solutions. Subsequent screening of the focused library, coupled with proteome analysis, led to the discovery of D008 as a small organic molecule as a small organic molecule with the ability to condensate a specific subset of RNA-binding proteins. In vitro experiments demonstrated that the D008-induced sequestration of RNA-binding proteins impeded mRNA translation. D008 may offer a unique opportunity for studying the condensations of RNA-binding proteins and for developing an unprecedented class of small molecules that control gene expression. Screening of a chemical library led to the discovery of D008, a self-assembling small molecule that sequesters a subset of RNA-binding proteins, thereby inhibiting mRNA translation. D008 may offer a unique opportunity for analyzing the condensations of RNA-binding proteins and for developing an unprecedented class of small molecules that control gene expression. [Display omitted]