Discovery of covalent prolyl oligopeptidase boronic ester inhibitors

Abstract

Over the past decade, many drug discovery endeavors have been invested in targeting the serine proteases prolyl oligopeptidase (POP) for the treatment of Alzheimer's and Parkinson's disease and, more recently, epithelial cancers. Our research group has focused on the discovery of reversible covalent inhibitors, namely nitriles, to target the catalytic serine residue in this enzyme. While there have been many inhibitors discovered containing a nitrile to covalently bind to the catalytic serine, we have been investigating others, particularly boronic acids and boronic esters, the latter of which have been largely unexplored as covalent warheads. Herein we report a series of computationally-designed POP boronic ester inhibitors. These nanomolar-potent, easilyaccessible (1-2 step syntheses) compounds could facilitate future biochemical and biological studies of this enzyme's role in neurodegenerative diseases and cancer progression.

Design and discovery of boronic acid drugs

“…Our own group has used boronic esters as prodrugs for their corresponding boronic acids. The basic buffer used in our assays hydrolyzed the (+)-pinanediol-protected boronic ester 23 (Figure 26A) to their respective free boronic acids within 20 minutes after mass spectroscopy analysis (Figure 26B) [114,117]. This study's results allow for a much more diverse scope of potential drugs in future medicinal chemistry endeavours: harsh conditions normally used to cleave boronic esters to free boronic acids (strong acid, BBr3/BCl3, fluoride, etc.)…”

“…The boronic acid therefore remained bound the cysteine residue in a pseudo-irreversible manner without the risk of a suicide inhibitor. In our own research, we have found that the replacement of nitriles in our compounds have increased both potency [117] and residence time in the active site of the enzyme prolyl oligopeptidase (POP) [114]. Figure 17A shows two of our inhibitors differing only in their electrophiles.…”

“…Figure 18: (A) 15 (teal) docked to POP (gray); (B) 16 (teal), hydrolyzed, docked to POP (gray). Compounds from Plescia et al [117] and are docked using FITTED [119][120][121].…”

Understanding the binding interaction between phenyl boronic acid P1 and sugars: determination of association and dissociation constants using S–V plots, steady‐state spectroscopic methods and molecular docking

“…Ligand docking was carried out using a ligand docking module and results were analyzed using an Extra Precision (XP) visualizer. [ 5–10 ] Synthetic chemical ligands are easier to work with, are of low cost and are stable, therefore researchers now use these instead of enzymes to address related problems. Boronic acid derivatives have been used extensively to design chemosensors because they bind strongly to diols on sugars.…”

“…[ 6 ] The interaction between diols and boronic acid has been the basis for development of fluorometric and colorimetric sensors that focus on determining diol‐containing compounds. [ 7–9 ] Special advantages of systems based on fluorescence are: (i) high sensitivity, (ii) no damage or harm to the host system, (iii) better results from fluorescence decay time, and (iv) structural information and knowledge on the microenvironment of the molecule can be obtained. [ 11–18 ]…”