19 research outputs found
A Motor Function for the DEAD-Box RNA Helicase, Gemin3, in Drosophila
The survival motor neuron (SMN) protein, the determining factor for spinal muscular atrophy (SMA), is complexed with a group of proteins in human cells. Gemin3 is the only RNA helicase in the SMN complex. Here, we report the identification of Drosophila melanogaster Gemin3 and investigate its function in vivo. Like in vertebrates, Gemin3 physically interacts with SMN in Drosophila. Loss of function of gemin3 results in lethality at larval and/or prepupal stages. Before they die, gemin3 mutant larvae exhibit declined mobility and expanded neuromuscular junctions. Expression of a dominant-negative transgene and knockdown of Gemin3 in mesoderm cause lethality. A less severe Gemin3 disruption in developing muscles leads to flightless adults and flight muscle degeneration. Our findings suggest that Drosophila Gemin3 is required for larval development and motor function
Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors
Objective: To determine the effect of matrix metalloproteinase (MMP) inhibitors in mono-iodoacetate-induced arthritis in rats. Design: The ability of compounds to inhibit MMPs in vitro was assessed kinetically using a quenched fluorescent substrate. Rats were injected with iodoacetate intraarticularly in one knee joint and damage to the tibial plateau was evaluated from digitized images captured using an image analyser and by histology. Collagenase and gelatinase activity in cartilage from iodoacetate injected knees were evaluated using 3H-rat type I collagen and gelatin zymography, respectively. Results: Collagenase and gelatinase activity significantly increased in the knee cartilage of rats injected with iodoacetate with peak activity by day 7. Three MMP inhibitors were examined for their efficacy in the rat iodoacetate-induced arthritis model. Significant (
Discovery and Optimization of Indolyl-Containing 4‑Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria
There exists an urgent medical need
to identify new chemical entities
(NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly
those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent
a novel class of nonfluoroquinolone inhibitors of bacterial type II
topoisomerases active against MDR Gram-negative bacteria. Herein,
we report on the discovery and structure–activity relationships
of a series of fused indolyl-containing 4-hydroxy-2-pyridones with
improved <i>in vitro</i> antibacterial activity against
fluoroquinolone resistant strains. Compounds <b>6o</b> and <b>6v</b> are representative of this class, targeting both bacterial
DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility
screen, compounds <b>6o</b> and <b>6v</b> showed improved
MIC<sub>90</sub> values against <i>Escherichia coli</i> (0.5–1
μg/mL) and <i>Acinetobacter baumannii</i> (8–16
μg/mL) compared to the precursor compounds. In a murine septicemia
model, both compounds showed complete protection in mice infected
with a lethal dose of <i>E. coli</i>
Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma
The structure of LX7101, a dual LIM-kinase
and ROCK inhibitor for
the treatment of ocular hypertension and associated glaucoma, is disclosed.
Previously reported LIM kinase inhibitors suffered from poor aqueous
stability due to solvolysis of the central urea. Replacement of the
urea with a hindered amide resulted in aqueous stable compounds, and
addition of solubilizing groups resulted in a set of compounds with
good properties for topical dosing in the eye and good efficacy in
a mouse model of ocular hypertension. LX7101 was selected as a clinical
candidate from this group based on superior efficacy in lowering intraocular
pressure and a good safety profile. LX7101 completed IND enabling
studies and was tested in a Phase 1 clinical trial in glaucoma patients,
where it showed efficacy in lowering intraocular pressure