Design, Synthesis, and Characterization of Nucleoside Based Probes to Evaluate the Role of Human Histidine Triad Nucleotide Binding Protein 1 in Mu Opioid Receptor and N-Methyl-DAspartate Receptor Cross Regulation

Abstract

The histidine triad nucleotide binding protein 1 (HINT1) is a nucleoside phosphoramidase thathas garnered interest due to its widespread expression and participation in a broad range of biological processes. Herein, we discuss the role of HINT1 as a regulator of several CNS functions, tumor suppressor, and mast cell activator via its interactions with multiple G-protein coupled receptors and transcription factors. Importantly, altered HINT1 expression and mutation is connected to the progression of multiple disease states, including several neuropsychiatric disorders, peripheral neuropathy, and tumorigenesis. Additionally, due to its involvement in the activation of several clinically used phosphoramidate prodrugs, tremendous efforts have been made to better understand the interactions behind nucleoside binding and phosphoramidate hydrolysis by HINT1. We detail the substrate specificity and catalytic mechanism of HINT1 hydrolysis while highlighting the structural biology behind these efforts. The aim of this review is to summarize the multitude of biological and pharmacological functions in which HINT1 participates, while addressing the areas of need for future research.