Identification of N,N-arylalkyl-picolinamide derivatives targeting the RNA-binding protein HuR, by combining biophysical fragment-screening and molecular hybridization.

Hu proteins are members of the RNA-binding protein (RBP) family and play a pivotal role in the regulation of post-transcriptional processes. Through interaction with selected mRNAs, RBPs regulate their function and stability; as a consequence, RBP dysregulation can cause abnormal translation of key proteins involved in several pathologies. In the past few years, this observation has sparked interest to develop new treatments against these pathologies by using small molecules able to modulate RBP activity. Among the four Hu proteins, we have directed our efforts towards the isoform HuR, which is mainly involved in cancer, inflammation and retinopathy. Aimed at developing compounds able to modulate the stability of HuR-mRNA complexes, in the present work, we applied a biophysical fragment screening by assessing a library of halogen-enriched heterocyclic fragments (HEFLibs) via Surface Plasmon Resonance (SPR) and Saturation Transfer Difference (STD) NMR to select promising fragments able to interact with HuR. One selected fragment and a few commercially available congeners were exploited to design and synthesize focused analogues of compound N-(3-chlorobenzyl)-N-(3,5-dihydroxyphenethyl)-4-hydroxybenzamide (1), our previously reported hit. STDNMR spectroscopy, molecular modeling, and SPR offered further insight into the HuR-small molecule interaction and showed that fragment-based approaches represent a promising and yet underexplored strategy to tackle such unusual targets. Lastly, fluorescence polarization (FP) studies revealed the capability of the new compounds to interfere with the formation of the HuR-mRNA complex. This is, to our knowledge, the first fragment-based campaign performed on the Hu protein class, and one of the few examples in the larger RBP field and constitutes an important step in the quest for the rational modulation of RBPs and related RNA functions by small molecules.

Plasma renin concentration as a predictor of outcome in a medical intensive care setting: a retrospective pilot study.

BACKGROUND: Renin and aldosterone are involved in an organ perfusion pathway that may be an estimate of disease severity. The primary objective was to explore the relationship between outcome and aldosterone and renin levels at medical intensive care unit (MICU) admissions in comparison to SAPS II scores. METHODS: This retrospective study was conducted on patients admitted to the adult MICU during 12 months. Exclusion: subjects with creatinine >176 mmol/l, chronic arrhythmia and ACE-inhibitor therapy. Admission aldosterone and renin plasma levels were measured and SAPS II scores were calculated. RESULTS: Eighty-two patients were included. Only the plasma renin median concentration difference between survivors and non-survivors was significant (P=0.0168). The area under the ROC curve for mortality and plasma renin concentration was similar to that of SAPS II. The correlation between mortality and renin >84 pg/mL showed an odds ratio of 5.78±3.45, P=0.003. CONCLUSION: Renin was correlated to outcome in critically ill medical patients.