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Synthesis, Characterization, and Screening of Signal Peptide Dependent Inhibitors of the Sec61 Channel
Date
2023Type
DissertationDepartment
Cell and Molecular Biology
Degree Level
Doctorate Degree
Abstract
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.
Permanent link
http://hdl.handle.net/11714/10887Additional Information
Committee Member | Chalifoux, Wesley A.; Ryan, Rob; Tal-Gan, Yftah |
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