Targeting RNA with small molecules is a major challenge of current medicinal chemistry, and the identification and design of original scaffolds able to selectively interact with an RNA target remains difficult. Various approaches have been developed based on classical medicinal chemistry strategies (fragment-based drug design, dynamic combinatorial chemistry, HTS or DNA-encoded libraries) as well as on advanced structural biology and biochemistry methodologies (such as X-ray, cryo-EM, NMR, or SHAPE). Here, we report the de novo design, synthesis, and biological evaluation of RNA ligands by using a straightforward and sustainable chemistry combined with molecular docking and biochemical and biophysical studies that allowed us to identify a novel pharmacophore for RNA binding. Specifically, we focused on targeting the biogenesis of microRNA-21, the well-known oncogene. This led us not only to promising inhibitors but also to a better understanding of the interactions between the small-molecule compounds and the RNA target paving the way for the rational design of efficient inhibitors with potential anticancer activity.

Laccases belong to a family of multicopper enzymes able to oxidize a broad spectrum of organic compounds. Despite the well‐known property of laccases to carry out bleaching and degradation of industrial dyes and polyphenolic compounds, their industrial use is often limited by the high cost, low efficiency, or instability of these enzymes. To look for new microorganisms which produce laccases that are potentially suitable for industrial applications, we have isolated several fungal strains from a cave in northern Spain. Their phenotypic analysis on agar plates supplemented with ABTS (2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) disclosed two laccase‐positive strains. Further genotyping revealed that they belonged to the Gliomastix murorum and Conidiobolus thromboides species. The secretion of G. murorum and C. thromboides laccase‐like enzymes was then confirmed by zymography. Further identification of these polypeptides by mass‐spectroscopy revealed the nature of the laccases and made it possible to predict their functional domains and other features. In addition, plate assays revealed that the laccases secreted by both G. murorum and C. thromboides were capable of degrading industrial dyes (Congo Red, Indigo, and Eriochrome Black T). Homology modeling and substrate docking predicted the putative structure of the currently uncrystallized G. murorum enzyme as well as its amino acid residues potentially involved in interactions with these dyes. In summary, new biochemical and structural insights into decolorization mediated by G. murorum laccase as well as identification of laccase‐like oxidase in C. thromboides point to a promising future for these enzymes in biotechnology.

The muscleblind-like protein family (MBNL) plays a prominent role in the regulation of alternative splicing. Consequently, the loss of MBNL function resulting from sequestration by RNA hairpins triggers the development of a neuromuscular disease called myotonic dystrophy (DM). Despite the sequence and structural similarities between the four zinc-finger domains that form MBNL1, recent studies have revealed that the four binding domains have differentiated splicing activity. The dynamic behaviors of MBNL1 ZnFs were simulated using conventional molecular dynamics (cMD) and steered molecular dynamics (sMD) simulations of a structural model of MBNL1 protein to provide insights into the binding selectivity of the four zinc-finger (ZnF) domains toward the GpC steps in YGCY RNA sequence. In accordance with previous studies, our results suggest that both global and local residue fluctuations on each domain have great impacts on triggering alternative splicing, indicating that local motions in RNA-binding domains could modulate their affinity and specificity. In addition, all four ZnF domains provide a distinct RNA-binding environment in terms of structural sampling and mobility that may be involved in the differentiated MBNL1 splicing events reported in the literature.