Pyrrolidine nucleoside bisphosphonates as antituberculosis agents targeting hypoxanthine-guanine phosphoribosyltransferase

0498560 - ÚOCHB 2019 RIV FR eng J - Článek v odborném periodiku
Eng, W. S. - Rejman, Dominik - Pohl, Radek - West, N. P. - Woods, K. - Naesens, L. M. J. - Keough, D. T. - Guddat, L. W.
Pyrrolidine nucleoside bisphosphonates as antituberculosis agents targeting hypoxanthine-guanine phosphoribosyltransferase.
European Journal of Medicinal Chemistry. Roč. 159, Nov 5 (2018), s. 10-22. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA MZd(CZ) NV17-29680A; GA ČR GA15-11711S
Institucionální podpora: RVO:61388963
Klíčová slova: Mycobacterium tuberculosis * therapeutic drug leads * X-ray crystal structures * hypoxanthine-guanine phosphoribosyltransferase * pyrrolidine nucleoside phosphonates * pyrrolidine nucleoside bisphosphonates * phosphoramidate prodrugs
Obor OECD: Organic chemistry
Impakt faktor: 4.833, rok: 2018

Therapeutic treatment of tuberculosis (TB) is becoming increasingly problematic due to the emergence of drug resistant Mycobacterium tuberculosis (Mt). Thus, new targets for anti-TB drug discovery need to be identified to combat and eradicate this disease. One such target is hypoxanthine-guanine phosphoribosyltransferase (HGPRT) which synthesises the 6-oxopurine nucleoside monophosphates essential for DNA/RNA production. [3R,4R]-4-Hypoxanthin-9-yl-3-( (S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine and [3R,4R-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine (compound 6) are the most potent inhibitors of MtHGPRT yet discovered having K-i values of 60 nM. The crystal structure of the MtHGPRT.6 complex was obtained and compared with that of human HGPRT in complex with the same inhibitor. These structures provide explanations for the 60-fold difference in the inhibition constants between these two enzymes and a foundation for the design of next generation inhibitors. In addition, crystal structures of MtHGPRT in complex with two pyrrolidine nucleoside phosphosphonate inhibitors plus pyrophosphate provide insights into the final stage of the catalytic reaction. As the first step in ascertaining if such compounds have the potential to be developed as anti-TB therapeutics, the tetra-(ethyl L-phenylalanine) tetraamide prodrug of 6 was tested in cell based assays. This compound arrested the growth of virulent Mt not only in its replicating phase (IC50 of 14 mu M) but also in its latent phase (IC50 of 29 mu M). Furthermore, it arrested the growth of Mt in infected macrophages (MIC50 of 85 mu M) and has a low cytotoxicity in mammalian cells (CC50 of 132 +/- 20 mu M). These inhibitors are therefore viewed as forerunners of new anti-TB chemotherapeutics.
Trvalý link: http://hdl.handle.net/11104/0290893