Nanomole Scale Screening of Fluorescent RNA-Methyltransferase Probes Enables the Discovery of METTL1 Inhibitors.

RNA methylation is a metabolic process validated for its association with various diseases, and thus, RNA methyltransferases (MTases) have become increasingly important in drug discovery. Yet, most frequently utilized RNA MTase assays are limited in their throughput and hamper this rapidly evolving field of medicinal chemistry. In this study, we describe a modular nanomole scale building block system that allowed the identification of tailored fluorescent MTase probes to unlock a broad selection of MTase drug targets for fluorescence-based binding assays.

Identification of Dual Inhibitors Targeting Main Protease (M) and Cathepsin L as Potential Anti-SARS-CoV-2 Agents.

In this structure-activity relationship (SAR) study, we report the development of dual inhibitors with antiviral properties targeting the SARS-CoV-2 main protease (M) and human cathepsin L (hCatL). The novel molecules differ in the aliphatic amino acids at the P2 site and the fluorine position on the phenyl ring at the P3 site. The identified dual inhibitors showed values within 1.

Ligand-Based Design of Selective Peptidomimetic uPA and TMPRSS2 Inhibitors with Arg Bioisosteres.

Trypsin-like serine proteases are involved in many important physiological processes like blood coagulation and remodeling of the extracellular matrix. On the other hand, they are also associated with pathological conditions. The urokinase-pwlasminogen activator (uPA), which is involved in tissue remodeling, can increase the metastatic behavior of various cancer types when overexpressed and dysregulated.

Improving binding entropy by higher ligand symmetry? - A case study with human matriptase.

Understanding different contributions to the binding entropy of ligands is of utmost interest to better predict affinity and the thermodynamic binding profiles of protein-ligand interactions and to develop new strategies for ligand optimization. To these means, the largely neglected effects of introducing higher ligand symmetry, thereby reducing the number of energetically distinguishable binding modes on binding entropy using the human matriptase as a model system, were investigated. A set of new trivalent phloroglucinol-based inhibitors that address the roughly symmetric binding site of the enzyme was designed, synthesized, and subjected to isothermal titration calorimetry.