Mechanistic Studies of Small Molecule Ligands Selective to RNA Single G Bulges.

Small-molecule RNA binders have emerged as an important pharmacological modality. A profound understanding of the ligand selectivity, binding mode, and influential factors governing ligand engagement with RNA targets is the foundation for rational ligand design. Here, we report a novel class of coumarin derivatives exhibiting selective binding affinity towards single G RNA bulges.

Rapid Characterization of Structural and Behavioral Changes of Therapeutic Proteins by Relaxation and Diffusion H-SOFAST NMR Experiments.

Biologic drugs have emerged as a rapidly expanding and important modality, offering promising therapeutic solutions by interacting with previously "undruggable" targets, thus significantly expanding the range of modern pharmaceutical applications. However, the inherent complexity of these drugs also introduces liabilities and poses challenges in their development, necessitating efficient screening methods to evaluate the structural stability and behavior. Although nuclear magnetic resonance (NMR) spectroscopy is well-suited for detecting weak interactions, changes in dynamics, high-order structure, and association states of macromolecules in fully formulated samples, the inherent low sensitivity limits its utility as a fast screening and characterization tool.

Transaminase-Catalyzed Synthesis of β-Branched Noncanonical Amino Acids Driven by a Lysine Amine Donor.

Transaminases are choice biocatalysts for the synthesis of chiral primary amines, including amino acids bearing contiguous stereocenters. In this study, we employ lysine as a "smart" amine donor in transaminase-catalyzed dynamic kinetic resolution reactions to access β-branched noncanonical arylalanines. Our mechanistic investigation demonstrates that, upon transamination, the lysine-derived ketone byproduct readily cyclizes to a six-membered imine, driving the equilibrium in the desired direction and thus alleviating the need to load superstoichiometric quantities of the amine donor or deploy a multienzyme cascade.

Dynamic sampling in autonomous process optimization.

Autonomous process optimization (APO) is a technology that has recently found utility in a multitude of process optimization challenges. In contrast to most APO examples in microflow reactor systems, we recently presented a system capable of optimization in high-throughput batch reactor systems. The drawback of APO in a high-throughput batch reactor system is the reliance on reaction sampling at a predetermined static timepoint rather than a dynamic endpoint.

Ultra-clean pure shift NMR with optimal water suppression for analysis of aqueous pharmaceutical samples.

Pure shift NMR experiments greatly enhance spectral resolution by collapsing multiplet structures into singlets and, with water suppression, can be used for aqueous samples. Here, we combine ultra-clean pure-shift NMR (SAPPHIRE) with two different internally encoded water suppression schemes to achieve optimal performance for small molecule and macrocyclic peptide pharmaceuticals in water and acetonitrile-water mixtures.