Covalent Labeling of Matrix Metalloproteases with Affinity-Based Probes Containing Tuned Reactive N-Acyl-N-Alkyl Sulfonamide Cleavable Linkers.

Original covalent probes with an N-acyl-N-alkyl sulfonamide cleavable linker were developed to target a broad set of human Matrix Metalloproteases (MMPs). The electrophilicity of this cleavable linker was modulated to improve the selectivity of the probes as well as reduce their unspecific reactivity in complex biological matrices. We first demonstrated that targeting the S subsite of MMPs enables access to broad-spectrum affinity-based probes that exclusively react with the active version of these proteases.

Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation.

Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to identify and optimize small molecule inhibitors of pathogenic fibroblast activation.

Diastereoselective Synthesis of Phosphinic Dipeptide Isosteres: Domino Chirality Transfer during a Stereocontrolled P-Michael Reaction.

A highly diastereoselective P-Michael addition of chiral aminophosphinic acids to achiral acrylates has been developed, leading to phosphinic dipeptide isosteres in high yields and dr of up to >50:1. The method allows for the diastereoselective preparation of target compounds without the need for chiral auxiliaries or P-chiral substrates. A possible mechanistic explanation involves a domino chirality transfer from the aminophosphinic acid to the P center, amplified by a crucial benzhydryl ester group, and then to the α-carbon.

Phosphinic Peptides as Tool Compounds for the Study of Pharmacologically Relevant Zn-Metalloproteases.

Phosphinic peptides constitute an important class of bioactive compounds that have found a wide range of applications in the field of biology and pharmacology of Zn-metalloproteases, the largest family of proteases in humans. They are designed to mimic the structure of natural substrates during their proteolysis, thus acting as mechanism-based, transition state analogue inhibitors. A combination of electrostatic interactions between the phosphinic acid group and the Zn cation as well as optimal noncovalent enzyme-ligand interactions can result in both high binding affinity for the desired target and selectivity against other proteases.