Chemical tools to expand the ligandable proteome: diversity-oriented synthesis-based photoreactive stereoprobes.

التفاصيل البيبلوغرافية
العنوان: Chemical tools to expand the ligandable proteome: diversity-oriented synthesis-based photoreactive stereoprobes.
المؤلفون: Ogasawara D, Konrad DB, Tan ZY, Carey KL, Luo J, Won SJ, Li H, Carter T, DeMeester KE, Njomen E, Schreiber SL, Xavier RJ, Melillo B, Cravatt BF
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 29. Date of Electronic Publication: 2024 Feb 29.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: Chemical proteomics enables the global assessment of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, been limited. Here, we describe a diversity-oriented synthesis (DOS)-inspired library of stereochemically-defined compounds bearing diazirine and alkyne units for UV light-induced covalent modification and click chemistry enrichment of interacting proteins, respectively. We find that these 'photo-stereoprobes' interact in a stereoselective manner with hundreds of proteins from various structural and functional classes in human cells and demonstrate that these interactions can form the basis for high-throughput screening-compatible nanoBRET assays. Integrated phenotypic analysis and chemical proteomics identified photo-stereoprobes that modulate autophagy by engaging the mitochondrial serine protease CLPP. Our findings show the utility of photo-stereoprobes for expanding the ligandable proteome, furnishing target engagement assays, and discovering and characterizing bioactive small molecules by cell-based screening.
تواريخ الأحداث: Date Created: 20240311 Latest Revision: 20240311
رمز التحديث: 20240311
مُعرف محوري في PubMed: PMC10925180
DOI: 10.1101/2024.02.27.582206
PMID: 38464067
قاعدة البيانات: MEDLINE
الوصف
DOI:10.1101/2024.02.27.582206