Synthesis and Kinetic Evaluation of Phosphomimetic Inhibitors Targeting Type B Ribose-5-Phosphate Isomerase from Mycobacterium Tuberculosis

18 Pages Posted: 14 Dec 2023

See all articles by Stéphanie Courtiol-Legourd

Stéphanie Courtiol-Legourd

Université Paris Saclay

Sandrine Mariano

Université Paris Saclay

Johanna Foret

Université Paris Saclay

Annette K. Roos

Uppsala University

Sherry L. Mowbray

Uppsala University

Laurent Salmon

Université Paris Saclay

Abstract

Because tuberculosis is still a major health threat worldwide, identification of new drug targets is urgently needed. In this study, we considered type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis as a potential target, and addressed known problems of previous inhibitors in terms of their sensitivity to hydrolysis catalyzed by phosphatase enzymes, which impaired their potential use as drugs. To this end, we synthesized six novel phosphomimetic compounds designed to be hydrolytically stable analogs of the substrate ribose 5-phosphate and the best known inhibitor 5-phospho-d-ribonate. The phosphate function was replaced by phosphonomethyl, sulfate, sulfonomethyl, or malonate groups. Inhibition was evaluated on type A and type B ribose-5-phosphate isomerases, and stability towards hydrolysis using alkaline phosphatase and veal serum was assessed. One of the phosphomimetic analogs, 5-deoxy-5-phosphonomethyl-d-ribonate, emerged as the first strong and specific inhibitor of the M. tuberculosis enzyme that is resistant to hydrolysis.

Keywords: enzyme inhibitors, phosphate, monosaccharides, ribose, isomerase, tuberculosis

Suggested Citation

Courtiol-Legourd, Stéphanie and Mariano, Sandrine and Foret, Johanna and Roos, Annette K. and Mowbray, Sherry L. and Salmon, Laurent, Synthesis and Kinetic Evaluation of Phosphomimetic Inhibitors Targeting Type B Ribose-5-Phosphate Isomerase from Mycobacterium Tuberculosis. Available at SSRN: https://ssrn.com/abstract=4655406 or http://dx.doi.org/10.2139/ssrn.4655406

Stéphanie Courtiol-Legourd

Université Paris Saclay ( email )

Sandrine Mariano

Université Paris Saclay ( email )

Johanna Foret

Université Paris Saclay ( email )

Annette K. Roos

Uppsala University ( email )

Box 513
Uppsala, 751 20
Sweden

Sherry L. Mowbray

Uppsala University ( email )

Box 513
Uppsala, 751 20
Sweden

Laurent Salmon (Contact Author)

Université Paris Saclay ( email )

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