Reversible and Fully Controllable Generation of Organo-Soluble DNA (osDNA).

The present work describes a complete and reversible transformation of DNA's properties allowing solubilization in organic solvents and subsequent chemical modifications that are otherwise not possible in an aqueous medium. Organo-soluble DNA (osDNA) moieties are generated by covalently linking a dsDNA fragment to a polyether moiety with a built-in mechanism, rendering the process perfectly reversible and fully controllable. The precise removal of the polyether moiety frees up the initial DNA fragment, unaltered, both in sequence and nature. The solubility of osDNA was confirmed in six organic solvents of decreasing polarity and six types of osDNAs. As a proof of concept, in the context of DNA-encoded library (DEL) technology, an amidation reaction was successfully performed on osDNA in 100% DMSO. The development of osDNA opens up entirely new avenues for any DNA applications that could benefit from working in nonaqueous solutions, including chemical transformations.

Impact of organic chemistry conditions on DNA durability in the context of DNA-encoded library technology.

High-power screening (HPS) technologies, such as DNA-encoded library (DEL) technology, could exponentially increase the dimensions of the chemical space accessible for drug discovery. The intrinsic fragile nature of DNA is associated with cumbersome limitations and DNA durability (e.g., depurination, loss of phosphate groups, adduct formation) is compromised in numerous organic chemistry conditions that require empirical testing. An atlas of reaction conditions (temperature, pH, solvent/buffer, ligands, oxidizing reagents, catalysts, scavengers in function of time) that have been systematically tested in multiple combinations, indicates precisely limits useful for DEL construction. More importantly, this approach could be used broadly to effectively evaluate DNA-compatibility of any novel on-DNA chemical reaction, and it is compatible with different molecular methodologies. This atlas and the general approach presented, by allowing novel reaction conditions to be performed in presence of DNA, should greatly help in expanding the DEL chemical space as well as any field involving DNA durability.

DNA-Compatible Suzuki-Miyaura Cross-Coupling Reaction of Aryl Iodides With (Hetero)Aryl Boronic Acids for DNA-Encoded Libraries.

An efficient method for the C-C bond formation via water soluble Na2PdCl4/sSPhos mediated Suzuki-Miyaura cross-coupling reaction of DNA-conjugated aryl iodide with (het)aryl boronic acids has been developed. This reaction proceeds at 37°C in water and acetonitrile (4:1) system. We also demonstrated that numerous aromatic and heteroaromatic boronic acids of different electronic natures, and harboring various functional groups, were highly compatible providing the desired coupling products in good to excellent yields. This DNA-compatible Suzuki-Miyaura cross-coupling reaction has strong potential to construct DNA-Encoded Libraries (DELs) in the context of drug discovery.

High-power screening (HPS) empowered by DNA-encoded libraries.

The world is totally dependent on medications. As science progresses, new, better, and cheaper drugs are needed more than ever. The pharmaceutical industry has been predominantly dependent on high-throughput screening (HTS) for the past three decades. Considering that the discovery rate has been relatively constant, can one hope for a much-needed sudden trend uptick? DNA-encoded libraries (DELs) and similar technologies, that have several orders of magnitude more screening power than HTS, and that we propose to group together under the umbrella term of high-power screening (HPS), are very well positioned to do exactly that. HPS also offers novel screening options such as parallel screening, ex vivo and in vivo screening, as well as a new path to druggable alternatives such as proteolysis targeting chimeras (PROTACs). Altogether, HPS unlocks novel powerful drug discovery avenues.

Paul Greengard: A persistent desire to comprehend the brain, and also to fix it.

Paul Greengard's name is and will remain profoundly associated with Neuroscience, with brain signaling and chemical transmission, with Parkinson's and Alzheimer's diseases, with fundamental discoveries and solving paradoxes, but much less perhaps with drug discovery. This should not be mistaken as disdain. Paul in fact did contemplate developing therapeutic avenues to actually treat brain diseases much more than it is known, perhaps during his entire career, and certainly over the last two decades. As a matter of fact, he did more than contemplate it, he directly and indirectly contributed in the development of treatments for neurological diseases and disorders. Paul's impact on fundamental aspects of the brain has been so gargantuan that any other aspect of Paul's life will have difficulty to shine. It is precisely this less known aspect of Paul's career that will be covered in this review. We will discover how Paul very early on moved away from biophysics to avoid working on nuclear weapons and instead started his career in the pharmacological spheres of a large pharmaceutical company.

Model-Informed Optimization of a Pediatric Clinical Pharmacokinetic Trial of a New Spironolactone Liquid Formulation.

Quantitative pharmacology brings important advantages in the design and conduct of pediatric clinical trials. Herein, we demonstrate the application of a model-based approach to select doses and pharmacokinetic sampling scenarios for the clinical evaluation of a novel oral suspension of spironolactone in pediatric patients with edema. A population pharmacokinetic model was developed and qualified for spironolactone and its metabolite, canrenone, using data from adults and bridged to pediatrics (2 to <17 years old) using allometric scaling. The model was then used via simulation to explore different dosing and sampling scenarios. Doses of 0.5 and 1.5 mg/kg led to target exposures (i.e., similar to 25 and 100 mg of the reference product in adults) in all the reference pediatric ages (i.e., 2, 6, 12 and 17 years). Additionally, two different sampling scenarios were delineated to accommodate patients into sparse sampling schemes informative to characterize drug pharmacokinetics while minimizing phlebotomy and burden to participating children.