Publications by authors named "Kimberley Yue"
Article Synopsis
- The Dengue virus NS5 polymerase is crucial for viral RNA synthesis and replication, making it a key drug target, yet few inhibitors for it have been developed compared to those for hepatitis C virus.
- Through a compound screening process, two new nonnucleoside inhibitors (NITD-434 and NITD-640) of DENV RdRp were identified, showing varying levels of inhibition in RNA polymerization and cellular assays.
- X-ray crystallography revealed that these compounds bind in the enzyme's RNA template tunnel, potentially impacting critical polymerase functions and suggesting new strategies for developing antiviral treatments against Dengue virus.
Article Synopsis
- SMARCA2 (BRM) is a key ATPase and member of the SWI/SNF chromatin-remodeling complex, which plays a crucial role in regulating gene expression alongside its relative, BRG1 (SMARCA4).
- Current research highlights the lack of small molecules that can specifically inhibit the ATPase activity of SWI/SNF, despite the relevance in cancer, particularly in BRG1-deficient cases.
- New allosteric dual inhibitors targeting both BRM and BRG1 have been developed, showing potential to reduce BRM-dependent gene expression and demonstrate anti-cancer effects in a BRG1-mutant lung tumor model, providing insights into SWI/SNF functions in various health contexts.
Article Synopsis
- Protein kinases have a common ATP-binding site, making it hard to find selective inhibitors; however, allosteric inhibitors that target less conserved areas could be more selective and effective under high ATP conditions.
- A screening method that focuses on high ATP concentrations can help identify inhibitors that bind outside the ATP pocket, which is a strategy we used with WNK kinases to find safer antihypertensive compounds.
- The research led to the discovery of several noncompetitive WNK1-4 kinase inhibitors, which were then optimized to show a specific binding mode and effectively inhibit a sodium transporter in kidney cells, aligning with the known functions of WNK kinases in electrolyte balance.
One of the central questions in the characterization of enzyme inhibitors is determining the mode of inhibition (MOI). Classically, this is done with a number of low-throughput methods in which inhibition models are fitted to the data. The ability to rapidly characterize the MOI for inhibitors arising from high-throughput screening in which hundreds to thousands of primary inhibitors may need to be characterized would greatly help in lead selection efforts.
View Article and Find Full Text PDFDengue virus (DENV) is the most significant mosquito-borne viral pathogen in the world and is the cause of dengue fever. The DENV RNA-dependent RNA polymerase (RdRp) is conserved among the four viral serotypes and is an attractive target for antiviral drug development. During initiation of viral RNA synthesis, the polymerase switches from a "closed" to "open" conformation to accommodate the viral RNA template.
View Article and Find Full Text PDFReporter gene assays (RGAs) are commonly used to measure biological pathway modulation by small molecules. Understanding how such compounds interact with the reporter enzyme is critical to accurately interpret RGA results. To improve our understanding of reporter enzymes and to develop optimal RGA systems, we investigated eight reporter enzymes differing in brightness, emission spectrum, stability, and substrate requirements.
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