Description
Title: Protein Kinase Deactivatable Bisubstrate Inhibitors
Abstract: Bivalent ligands are conjugates of pharmacophores that simultaneously target two binding sites of the biomolecule, such as bisubstrate inhibitors. Such structures provide feasible ways to create compounds whose capacity to bind to the biological target may be controlled by an outside stimulus. By coupling the pharmacophores with linkers that could be severed in response to outside stimuli, two basophilic protein kinase (PK) deactivatable bisubstrate inhibitors were created in the current study. The linker structure of the inhibitor ARC-2121 included a photo cleavable nitrodibenzofuran-comprising -amino acid residue. Through a reduction-cleavable disulfide bond, the pharmacophores of the other deactivatable inhibitor, ARC-2194, were conjugated. HPLC-MS was used to track the inhibitors’ disassembly. An equilibrium competitive displacement assay and an enzyme activity assay were used to determine the inhibitors’ affinity and inhibitory potency toward cAMP-dependent PK (PKAc). The 1-2-picomolar affinity of the deactivatable inhibitors toward PKAc was remarkably high. After ARC-2121 was exposed to 365 nm UV radiation, reaction products had an affinities that were 30 times lower. The affinity of ARC-2194 decreased by more than four orders of magnitude as a result of chemical reduction. These pharmacologically significant enzymes can be temporally inhibited or captured using the deactivatable inhibitors of PKs.
Keywords: protein kinase; deactivatable inhibitor; photocage; bivalent; bisubstrate; multivalent; stimuli-responsive
Paper Quality: SCOPUS / Web of Science Level Research Paper
Subject: Chemistry
Writer Experience: 20+ Years
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