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Synthesis, Characterization, and Screening of Signal Peptide Dependent Inhibitors of the Sec61 Channel
Cell and Molecular Biology
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The classic approaches to medicinal chemistry have been greatly successful for the production of therapeutics in modern times. The most successful approach has been using small molecules to target proteins to disrupt their function. Most of these therapeutic targets fall in a narrow range of protein classes and have left many potential therapeutic targets without successfully developed drugs. New approaches will be necessary to fill this need. The Sec61 translocon channel located in the ER membrane provides a passageway for entry into the ER lumen or integration into the ER membrane for a large percentage of human proteins. A few compounds have been discovered to block translocation of proteins through this channel, but most are not specific and too toxic for development into drugs. Cyclotriazadisulfonamide (CADA) is so far the most specific inhibitor of the Sec61 mediated translocation owing largely to its unique ability to bind specific amino acid residues with the hydrophobic α-helical H-region of signal peptides. Signal peptides (SPs) are unique tags on the N-terminus of proteins which target them to the Sec61 channel for translocation. The purpose of this dissertation was to synthesize new CADA analogues with improved potency, explore the mechanism of action of TL020 towards reduction of HBV replication, and develop novel screening platforms for CADA analogues. The strength of the dipole moment in its sidearm constituents has been shown to correlate with potency, likely owing to this specific interaction with the SP. Towards the first goal, nine new CADA analogues were synthesized with strong dipole moments in their sidearms to make highly potent CADA analogues. New and previously synthesized compounds were tested for their drug like properties of solubility, membrane permeability, and toxicity. CADA and its analogues are currently being developed as novel therapeutic agents for several diseases 3 including infection by hepatitis B virus (HBV). Towards the second goal, the effects on protein and mRNA expression levels of the potent CADA analogue, TL020, were explored on liver cells in an attempt to better understand the specificity and anti-HBV mechanism of action. Owing to the unique mechanism of CADA analogues it was necessary to develop novel screening assays to expand the list of disease targets for CADA analogues. Towards the third goal, cell-based assays were developed in 96-well plate format for finding potent drugs for SARS-CoV-2 and preterm labor. CADA has opened up a new window of possibilities for medicinal chemistry and it is possible that many other conditions can be targeted in the future by this novel approach.