Synthesis and kinetic evaluation of phosphomimetic inhibitors targeting type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis

Courtiol-Legourd, StephanieUniv Paris Saclay, Inst Chim Mol & Mat Orsay, CNRS, F-91400 Orsay, France. (author)

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 -5phosphate 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.

Mariano, SandrineUniv Paris Saclay, Inst Chim Mol & Mat Orsay, CNRS, F-91400 Orsay, France. (author)
Foret, JohannaUniv Paris Saclay, Inst Chim Mol & Mat Orsay, CNRS, F-91400 Orsay, France. (author)
Roos, Annette K.Uppsala universitet,Science for Life Laboratory, SciLifeLab,Strukturbiologi(Swepub:uu)anroo424 (author)
Mowbray, Sherry L,1954-Uppsala universitet,Institutionen för cell- och molekylärbiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)shmow020 (author)
Salmon, LaurentUniv Paris Saclay, Inst Chim Mol & Mat Orsay, CNRS, F-91400 Orsay, France. (author)
Univ Paris Saclay, Inst Chim Mol & Mat Orsay, CNRS, F-91400 Orsay, France.Science for Life Laboratory, SciLifeLab (creator_code:org_t)

By the author/editor: Courtiol-Legourd ...; Mariano, Sandrin ...; Foret, Johanna; Roos, Annette K.; Mowbray, Sherry ...; Salmon, Laurent

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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