1. New molecules and mechanisms that control RNA splicing
Target diseases: spinal muscular atrophy, autoimmune diseases
It is estimated that more than 80% of disease-modifying proteins are "undruggable" by small molecules due to lack of suitable ligand-binding pockets. This leaves a significant portion of diseases and biological processes out of our control. To create innovative solutions for the "undruggability" problem, we are developing a new class of molecules that acts via targeting precursor mRNAs and altering RNA splice patterns. These splicing modulators are an emerging pharmacological modality to regulate gene expression and RNA stability.
1. CRISPR-mediated Enzyme Fragment Complementation Assay for Quantification of the Stability of Splice Isoforms. ChemBioChem 23(9), e202200012 (2022). Tang Z#, Hegde S#, Zhao J#, Zhu S, Johnson KA, Lorson CL, Wang J*. 2. Recognition of single-stranded nucleic acids by small-molecule splicing modulators. Nucleic Acids Res., 49(14), 7870 (2021). Tang Z, Akhter S#, Ramprasad A#, Wang X#, Reibarkh M, Wang J, Aryal S, Thota SS, Zhao J, Douglas JT, Gao P, Holmstrom ED, Miao Y*, Wang J*. 3. Mechanistic studies of a small molecule modulator of SMN2 splicing, PNAS, 115(20): E4604-12 (2018). Wang J, Schultz PG, Johnson KA.
2. Bifunctional chimeric molecules, making 1 + 1 > 2
Target diseases: viral infection, neurodegenerative diseases
Covalent tethering of two functional fragments into one bifunctional molecule provides unique opportunities for mounting new functions on macromolecule substrates (e.g., RNAs). These chimeric molecules can be used to regulate biological processes that cannot be achieved by the two individual fragments separately, and therefore, 1 + 1 > 2. Our lab is developing novel chimeric molecules for regulating gene transcription, splicing, and expression.
1. Rapafucins, rapamycin-inspired macrocycles with new target specificity. Nat. Chem.,11(3):254-63 (2019). Guo ZF#, Hong SY#, Wang J#, Rehan S, Liu W, Peng H, Das M, Li W, Bhat S, Peiffer B, Ullman BR, Tse CM, Tarmakova Z, Schiene-Fischer C, Fischer G, Coe I, Paavilainen VO, Sun Z, Liu JO. 2. Discovery of a potent GLUT inhibitor using rapafucin 3D microarrays. (2019) Angew. Chem. Int. Ed. 58,17158–62. Guo ZF#, Cheng Z#, Wang J#, Liu W, Peng H, Wang Y, Rao AVS, Li RJ, Ying X, Korangath P, Liberti MV, Li Y, Xie Y, Hong SY, Schiene-Fischer C, Fischer G, Locasale JW, Sukumar S, Zhu H, Liu JO. 3. (Review) Inhibition of SARS-CoV-2 by targeting conserved viral RNA structures and sequences. Front. Chem., 9:802766 (2021). Hegde S#, Tang Z#, Zhao J, and Wang J*.
3. New compounds and pathways to modulate human immunity
Target disease: cancer, autoimmune diseases
Recently, immunomodulators have become a major direction in drug development to treat cancer and autoimmune diseases. Our group is interested in modulating interferon signaling pathways and uncovering new biological mechanisms and chemical space for immunotherapies.
1. Cellular Target Deconvolution of Small Molecules using a Selection-based Genetic Screening Platform. ACS Cent. Sci., 8(10), 1424-1434 (2022). Zhao J, Tang Z⁺⁺, Selvaraju M⁺⁺, Johnson KA, Douglas JT, Gao PF, Petrassi, HM, Wang MZ, Wang J*.