Dynamic docking of small molecules targeting RNA CUG repeats causing myotonic dystrophy type 1.

Expansion of RNA CUG repeats causes myotonic dystrophy type 1 (DM1). Once transcribed, the expanded CUG repeats strongly attract muscleblind-like 1 (MBNL1) proteins and disturb their functions in cells. Because of its unique structural form, expanded RNA CUG repeats are prospective drug targets, where small molecules can be utilized to target RNA CUG repeats to inhibit MBNL1 binding and ameliorate DM1-associated defects.

CHARMM-GUI Implicit Solvent Modeler for Various Generalized Born Models in Different Simulation Programs.

Implicit solvent models are widely used because they are advantageous to speed up simulations by drastically decreasing the number of solvent degrees of freedom, which allows one to achieve long simulation time scales for large system sizes. CHARMM-GUI, a web-based platform, has been developed to support the setup of complex multicomponent molecular systems and prepare input files. This study describes an (ISM) in CHARMM-GUI for various generalized Born (GB) implicit solvent simulations in different molecular dynamics programs such as AMBER, CHARMM, GENESIS, NAMD, OpenMM, and Tinker.

Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(GC) repeat expansion in vitro and in vivo ALS models.

The most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) is an expanded GC RNA repeat [r(GC)] in chromosome 9 open reading frame 72 (), which elicits pathology through several mechanisms. Here, we developed and characterized a small molecule for targeted degradation of r(GC). The compound was able to selectively bind r(GC)’s structure and to assemble an endogenous nuclease onto the target, provoking removal of the transcript by native RNA quality control mechanisms.

Massively Parallel Optimization of the Linker Domain in Small Molecule Dimers Targeting a Toxic r(CUG) Repeat Expansion.

RNA contributes to disease pathobiology and is an important therapeutic target. The downstream biology of disease-causing RNAs can be short-circuited with small molecules that recognize structured regions. The discovery and optimization of small molecules interacting with RNA is, however, challenging.

A general fragment-based approach to identify and optimize bioactive ligands targeting RNA.

RNAs have important functions that are dictated by their structure. Indeed, small molecules that interact with RNA structures can perturb function, serving as chemical probes and lead medicines. Here we describe the development of a fragment-based approach to discover and optimize bioactive small molecules targeting RNA.

A Small Molecule that Binds an RNA Repeat Expansion Stimulates Its Decay via the Exosome Complex.

Many diseases are caused by toxic RNA repeats. Herein, we designed a lead small molecule that binds the structure of the r(CUG) repeat expansion [r(CUG)] that causes myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD) and rescues disease biology in patient-derived cells and in vivo. Interestingly, the compound's downstream effects are different in the two diseases, owing to the location of the repeat expansion.

Development of a coarse-grained lipid model, LIME 2.0, for DSPE using multistate iterative Boltzmann inversion and discontinuous molecular dynamics simulations.

We suggest an improved version of the intermediate resolution implicit solvent model for lipids, LIME, that was previously developed for use with discontinuous molecular dynamics (DMD) simulations. LIME gets its geometrical and the energy parameters between bonded and nonbonded pairs of coarse-grained (CG) sites from atomistic simulations. The improved model, LIME 2.

Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold-small molecule interactions.

Vascular endothelial growth factor A (VEGFA) stimulates angiogenesis in human endothelial cells, and increasing its expression is a potential treatment for heart failure. Here, we report the design of a small molecule (TGP-377) that specifically and potently enhances VEGFA expression by the targeting of a non-coding microRNA that regulates its expression. A selection-based screen, named two-dimensional combinatorial screening, revealed preferences in small-molecule chemotypes that bind RNA and preferences in the RNA motifs that bind small molecules.

Macrocyclization of a Ligand Targeting a Toxic RNA Dramatically Improves Potency.

RNA molecules both contribute to and are causative of many human diseases. One method to perturb RNA function is to target its structure with small molecules. However, discovering bioactive ligands for RNA targets is challenging.

Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer.

As the area of small molecules interacting with RNA advances, general routes to provide bioactive compounds are needed as ligands can bind RNA avidly to sites that will not affect function. Small-molecule targeted RNA degradation will thus provide a general route to affect RNA biology. A non-oligonucleotide-containing compound was designed from sequence to target the precursor to oncogenic microRNA-21 (pre-miR-21) for enzymatic destruction with selectivity that can exceed that for protein-targeted medicines.

In vitro biosynthesis of metal nanoparticles in microdroplets.

We report the use of a hydrogel polymer, recombinant Escherichia coli cell extracts, and a microdroplet-based microfluidic device to fabricate artificial cellular bioreactors which act as reactors to synthesize diverse metal nanoparticles (NPs). The combination of cell extracts, microdroplet-based microfluidic device, and hydrogel was able to produce a mass amount of artificial cellular bioreactors with uniform size and shape. For the first time, we report the alternating generation of microdroplets through one orifice for the fabrication of the artificial cellular reactors using the cell extract as inner cellular components and hydrogel as an artificial cellular membrane.

Ultrasound-aided formation of gold nanoparticles on multi-walled carbon nanotubes functionalized with mercaptobenzene moieties.

A hybrid of multi-walled carbon nanotube (MWCNT) and gold nanoparticle (Au NP) was prepared under ultrasound irradiation. The approach starts with the functionalization of the walls of MWCNTs with mercaptobenzene moieties for the subsequent immobilization of Au NPs. From the Raman spectra, mercaptobenzene was proven to exist on the MWCNTs.

Organoclay-assisted interfacial polymerization for microfluidic production of monodisperse PEG-microdroplets and in situ encapsulation of E. coli.

We developed a novel one-pot synthetic strategy for preparing monodisperse polyethylene glycol diacrylate (PEGDA) microdroplets via organoclay-assisted interfacial polymerization approach for Escherichia coli encapsulation. Based on the mechanism of spontaneous and rapid polymerization of PEGDA precursor solution with Mg-organoclay, the prepared PEGDA microdroplets have uniform size and fine round shape, with size range of 74-118 µm. The size of microdroplets can be controlled through the changing continuous phase flow rate.

Synthesis and utilization of E. coli-encapsulated PEG-based microdroplet using a microfluidic chip for biological application.

We report herein an effective strategy for encapsulating Escherichia coli in polyethylene glycol diacrylate (PEGDA) microdroplets using a microfluidic device and chemical polymerization. PEGDA was employed as a reactant due to the biocompatibility, high porosity, and hydrophilic property. The uniform size and shape of microdroplets are obtained in a single-step process using microfluidic device.