Repurposing existing drugs: identification of irreversible IMPDH inhibitors by high-throughput screening. (1st January 2019)

• Record Type: Journal Article
• Authors: Sarwono, Albertus Eka Yudistira; Mitsuhashi, Shinya; Kabir, Mohammad Hazzaz Bin; Shigetomi, Kengo; Okada, Tadashi; Ohsaka, Fumina; Otsuguro, Satoko; Maenaka, Katsumi; Igarashi, Makoto; Kato, Kentaro; Ubukata, Makoto
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 171
• Page End: 178
• Publication Date: 2019-01-01
• Subjects: Drug repurposing -- IMP dehydrogenase -- irreversible inhibitors -- purine metabolic pathway; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2018.1540474
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Inosine 5′-monophosphate dehydrogenase (IMPDH) is an essential enzyme for the production of guanine nucleotides. Disruption of IMPDH activity has been explored as a therapeutic strategy for numerous purposes, such as for anticancer, immunosuppression, antiviral, and antimicrobial therapy. In the present study, we established a luciferase-based high-throughput screening system to identify IMPDH inhibitors from our chemical library of known bioactive small molecules. The screening of 1400 compounds resulted in the discovery of three irreversible inhibitors: disulfiram, bronopol, and ebselen. Each compound has a distinct chemical moiety that differs from other reported IMPDH inhibitors. Further evaluation revealed that these compounds are potent inhibitors of IMPDHs with k on values of 0.7 × 10 4 to 9.3 × 10 4 M −1 ·s −1 . Both disulfiram and bronopol exerted similar degree of inhibition to protozoan and mammalian IMPDHs. Ebselen showed an intriguing difference in mode of inhibition for different IMPDHs, with reversible and irreversible inhibition to each Cryptosporidium parvum IMPDH and human IMPDH type II, respectively. In the preliminary efficacy experiment against cryptosporidiosis in severe combined immunodeficiency (SCID) mouse, a decrease in the number of oocyst shed was observed upon the oral administration of disulfiram and bronopol, providing an early clinical proof-of-concept for further utilization of these compounds as IMPDH inhibitors.