2 research outputs found
Discovery of a Small-Molecule Modulator of Glycosaminoglycan Sulfation
Glycosaminoglycans
(GAGs) play critical roles in diverse processes
ranging from viral infection to neuroregeneration. Their regiospecific
sulfation patterns, which are generated by sulfotransferases, are
key structural determinants that underlie their biological activity.
Small-molecule modulators of these sulfotransferases could serve as
powerful tools for understanding the physiological functions of GAGs,
as well as potential therapeutic leads for human diseases. Here, we
report the development of the first cell-permeable, small-molecule
inhibitor selective for GAG sulfotransferases, which was obtained
using a high-throughput screen targeted against Chst15, the sulfotransferase
responsible for biosynthesis of chondroitin sulfate-E (CS-E). We demonstrate
that the molecule specifically inhibits GAG sulfotransferases <i>in vitro</i>, decreases CS-E and overall sulfation levels on
cell-surface and secreted chondroitin sulfate proteoglycans (CSPGs),
and reverses CSPG-mediated inhibition of axonal growth. These studies
pave the way toward a new set of pharmacological tools for interrogating
GAG sulfation-dependent processes and may represent a novel therapeutic
approach for neuroregeneration
Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase‑1 in Cells
Methionine
aminopeptidases (MetAPs), which remove the initiator
methionine from nascent peptides, are essential in all organisms.
While MetAP2 has been demonstrated to be a therapeutic target for
inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell
proliferation. Our earlier efforts identified two structural classes
of human MetAP1 (<i>Hs</i>MetAP1)-selective inhibitors (<b>1</b>–<b>4</b>), but all of them failed to inhibit
cellular <i>Hs</i>MetAP1. Using Mn(II) or Zn(II) to activate <i>Hs</i>MetAP1, we found that <b>1</b>–<b>4</b> could only effectively inhibit purified <i>Hs</i>MetAP1
in the presence of physiologically unachievable concentrations of
Co(II). In an effort to seek Co(II)-independent inhibitors, a novel
structural class containing a 2-(pyridin-2-yl)quinazoline core has
been discovered. Many compounds in this class potently and selectively
inhibited <i>Hs</i>MetAP1 without Co(II). Subsequently,
we demonstrated that <b>11j</b>, an auxiliary metal-dependent
inhibitor, effectively inhibited <i>Hs</i>MetAP1 in primary
cells. This is the first report that an <i>Hs</i>MetAP1-selective
inhibitor is effective against its target in cells