3 research outputs found
S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis)
<p>Abstract</p> <p>Background</p> <p>S110 is a novel dinucleoside analog that could have advantages over existing DNA methyltransferase (DNMT) inhibitors such as decitabine. A potential therapeutic role for S110 is to increase fetal hemoglobin (HbF) levels to treat β-hemoglobinopathies. In these experiments the effect of S110 on HbF levels in baboons and its ability to reduce DNA methylation of the γ-globin gene promoter in vivo were evaluated.</p> <p>Methods</p> <p>The effect of S110 on HbF and γ-globin promoter DNA methylation was examined in cultured human erythroid progenitors and in vivo in the baboon pre-clinical model. S110 pharmacokinetics was also examined in the baboon model.</p> <p>Results</p> <p>S110 increased HbF and reduced DNA methylation of the γ-globin promoter in human erythroid progenitors and in baboons when administered subcutaneously. Pharmacokinetic analysis was consistent with rapid conversion of S110 into the deoxycytosine analog decitabine that binds and depletes DNA.</p> <p>Conclusion</p> <p>S110 is rapidly converted into decitabine, hypomethylates DNA, and induces HbF in cultured human erythroid progenitors and the baboon pre-clinical model.</p
A Time-Resolved SERS Study of the Adsorption and Electrochemical Reduction of 4-Pyridinecarboxaldehyde and 4-(Hydroxymethyl)pyridine
Discovery of Novel Putative Inhibitors of UDP-GlcNAc 2‑Epimerase as Potent Antibacterial Agents
We
present the discovery and optimization of a novel series of inhibitors
of bacterial UDP-<i>N</i>-acetylglucosamine 2-epimerase
(called 2-epimerase in this letter). Starting from virtual screening
hits, the activity of various inhibitory molecules was optimized using
a combination of structure-based and rational design approaches. We
successfully designed and identified a 2-epimerase inhibitor (compound <b>12-ES-Na,</b> that we named Epimerox), which blocked the growth
of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)
at 3.9 μM MIC (minimum inhibitory concentration) and showed
potent broad-range activity against all Gram-positive bacteria that
were tested. Additionally a microplate coupled assay was performed
to further confirm that the 2-epimerase inhibition of Epimerox was
through a target-specific mechanism. Furthermore, Epimerox demonstrated
in vivo efficacy and had a pharmacokinetic profile that is consonant
with it being developed into a promising new antibiotic agent for
treatment of infections caused by Gram-positive bacteria