Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics

Lipids play critical roles in cell biology, often through direct interactions with proteins. We recently described the use of photoreactive lipid probes combined with quantitative mass spectrometry to globally map lipid–protein interactions, and the effects of drugs on these interactions, in cells. Here, we investigate the broader potential of lipid-based chemical proteomic probes for determining the cellular targets of biologically active small molecules, including natural product derivatives and repurposed drugs of ill-defined mechanisms. We identify the prostaglandin-regulatory enzyme PTGR2 as a target of the antidiabetic hops derivative KDT501 and show that miconazolean antifungal drug that attenuates disease severity in preclinical models of multiple sclerosisinhibits SGPL1, an enzyme that degrades the signaling lipid sphingosine-1-phosphate, drug analogues of which are used to treat multiple sclerosis in humans. Our findings highlight the versatility of lipid-based chemical proteomics probes for mapping small molecule–protein interactions in human cells to gain mechanistic understanding of bioactive compounds

Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial

<div><p>Objective</p><p>The aim of this prospective multicenter randomized controlled trial was to compare the efficacy of silver nitrate cauterization against that of topical steroid ointment in the treatment of neonatal umbilical granuloma.</p><p>Methods</p><p>An open-label, non-inferiority randomized controlled trial was conducted from January 2013 to January 2016. The primary endpoint for the silver nitrate cauterization and topical steroid ointment groups was the healing rate after 2 weeks of treatment, applying a non-inferiority margin of 10%. The healing rate was evaluated until completion of 3 weeks of treatment.</p><p>Results</p><p>Participants comprised 207 neonates with newly diagnosed umbilical granuloma, randomized to receive silver nitrate cauterization (n = 104) or topical steroid ointment (n = 103). Healing rates after 2 weeks of treatment were 87.5% (91/104) in the silver nitrate cauterization and 82% (82/100) in the topical steroid ointment group group. The difference between groups was -5.5% (95% confidence interval, -19.1%, 8.4%), indicating that the non-inferiority criterion was not met. After 3 weeks of treatment, the healing rate with topical steroid ointment treatment was almost identical to that of silver nitrate cauterization (94/104 [90.4%] vs. 91/100 [91.0%]; 0.6% [-13.2 to 14.3]). No major complications occurred in either group.</p><p>Conclusions</p><p>This study did not establish non-inferiority of topical steroid ointment treatment relative to silver nitrate cauterization, presumably due to lower healing rates than expected leading to an underpowered trial. However, considering that silver nitrate cauterization carries a distinct risk of chemical burns and that the overall efficacy of topical steroid ointment treatment is similar to that of silver nitrate cauterization, topical steroid ointment might be considered as a good alternative in the treatment of neonatal umbilical granuloma due to its safety and simplicity. To clarify non-inferiority, a larger study is needed.</p></div

CONSORT flow diagram.

<p>Progression of patients through the trial up to 3 weeks of treatment in all participating centers. No patients dropped out due to adverse events in either group.</p

Umbilical granuloma healing rate after 1, 2 and 3 weeks of treatment.

<p>Umbilical granuloma healing rate after 1, 2 and 3 weeks of treatment.</p

Baseline characteristics of patients.

<p>Baseline characteristics of patients.</p