Abstract: Vicinal (1,2-disubstituted) functional group motifs are ubiquitous in structurally complex small molecules that are of academic and industrial importance, including many widely used pharmaceutical agents. Many such functional group combinations, however, remain exceptionally challenging to synthesize. The goal of research in the Engle lab is to develop a general catalytic platform for alkene and alkyne difunctionalization to introduce a diverse array of functional groups at each of the two carbon atoms in a programmable fashion.
The applications of functional nanomaterials towards biological interfacing continue to emerge in various fields, such as in drug delivery and tissue engineering. While the rational control of surface chemistry and mechanical properties have been achieved for several of these biocompatible systems, these biomaterials are rarely synthesized with optical and electronic functionalities that could be beneficial for controlling the behavior of excitable cells (e.g., neurons and cardiac cells) or for biosensing applications.
Post-translational modification of histone proteins, including lysine methylation and acylation, regulate gene expression through recruitment of reader proteins to the nucleosome. Dysregulation of these events is prevalent in a wide range of diseases, such that there is much interest in characterizing these modifications and their binding partners. We have used both supramolecular chemistry and protein engineering approaches to study the protein-protein interactions that are mediated by these post-translational modifications and to develop new tools to sense them.
The fidelity of intracellular signaling pathways requires that cells control the production of signaling agents in space and in time. Phosphatidic acid (PA) is both a central phospholipid biosynthetic intermediate and a multifunctional lipid second messenger produced at several discrete subcellular locations. The modes of action of PA can differ based on upstream stimulus, biosynthetic source, and site of production. How cells regulate the local production of PA to direct diverse signaling outcomes remains elusive.
Abstract Body: Non-adherence is a major hurdle for the effective treatment of HIV, a global epidemic even after 30 years of medical advancements. Long-acting therapeutics have the potential to improve adherence through simplified regimens. One such investigational medication is MK-8591, a nucleoside reverse transcriptase translocation inhibitor with subnanomolar antiviral activity and a long intracellular half-life. To support this program, a world-class manufacturing synthesis which is robust, green, and sustainable was targeted.