Design and Synthesis of Non-Peptidic Transcription Factors.-

Chemical Biology;Organic Chemistry;Transcription;Biological Chemistry;Chemistry;Science;Chemistry

Casey, Ryan J.Sanford, Melaine S. ;

University of Michigan

关键词: Chemical Biology;    Organic Chemistry;    Transcription;    Biological Chemistry;    Chemistry;    Science;    Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/75818/rjcasey_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Transcription is important for the determination of cellular phenotype through theregulation of gene expression and its mis-regulation can lead to abnormal cell function.Transcriptional activators are essential for high fidelity transcription, responsible forseeking out particular genes and up-regulating them to precise levels in a signalresponsivefashion. Molecules that can reconstitute the function of transcriptionalactivators, artificial transcription activators, are highly desirable commodities asmechanistic tools and transcription-based therapeutics. Transcriptional activators controlthe specificity and extent of gene upregulation through two domains: the DNA bindingdomain (DBD) confers specific binding to DNA and the transcriptional activation domain(TAD) dictates the level of gene expression. Many questions surrounding how naturaltranscriptional activation domains function has hindered the development of TADreplacements despite their likely advantages in terms of stability, delivery, and and/orimmunogenic properties.To address the need for the development and characterization of small moleculexvTADs we have employed a combination of organic chemistry and biological evaluationsto produce a class of isoxazolidines that functionally mimic natural TADs. We identifiedthe first small molecule, an amphipathic isoxazolidine, that reconstitutes transcription inliving cell culture. Additionally, the amphipathic isoxazoldine alone can competitivelyinhibit the DNA localized-isoxazolidine, indicating that it is the isoxazolidine moiety thatmakes contacts with the transcriptional machinery that are important for activation. Manydifferent peptide sequences can function as activators and we hypothesized this featurewould translate to other suitably functionalized small molecules. Indeed, otherisoxazolidine and non-isoxazolidine TADs activated transcription in cell culture. With anarray of small molecule TADs, we designed activator artificial transcription factors andtested them for activation in cell culture.