7ZSR

purine nucleoside phosphorylase in complex with JS-379

Summary for 7ZSR

• Entry DOI: 10.2210/pdb7zsr/pdb
• Descriptor: Purine nucleoside phosphorylase, [(~{E})-2-[5-bromanyl-2-[(4-oxidanylidene-3,5-dihydropyrrolo[3,2-d]pyrimidin-7-yl)sulfanyl]phenyl]ethenyl]phosphonic acid, ACETATE ION, ... (4 entities in total)
• Functional Keywords: pnp-inhibitor complex, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 3
• Total formula weight: 84163.90

Authors

Djukic, S.,Pachl, P.,Rezacova, P. (deposition date: 2022-05-08, release date: 2023-05-17, Last modification date: 2024-02-07)

Primary citation

Skacel, J.,Djukic, S.,Baszczynski, O.,Kalcic, F.,Bilek, T.,Chalupsky, K.,Kozak, J.,Dvorakova, A.,Tloust'ova, E.,Kral'ova, Z.,Smidkova, M.,Voldrich, J.,Rumlova, M.,Pachl, P.,Brynda, J.,Vuckova, T.,Fabry, M.,Snasel, J.,Pichova, I.,Rezacova, P.,Mertlikova-Kaiserova, H.,Janeba, Z.
Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors.
J.Med.Chem., 66:6652-6681, 2023

PubMed Abstract: Purine nucleoside phosphorylase (PNP) is a well-known molecular target with potential therapeutic applications in the treatment of T-cell malignancies and/or bacterial/parasitic infections. Here, we report the design, development of synthetic methodology, and biological evaluation of a series of 30 novel PNP inhibitors based on acyclic nucleoside phosphonates bearing a 9-deazahypoxanthine nucleobase. The strongest inhibitors exhibited IC values as low as 19 nM (human PNP) and 4 nM ( () PNP) and highly selective cytotoxicity toward various T-lymphoblastic cell lines with CC values as low as 9 nM. No cytotoxic effect was observed on other cancer cell lines (HeLa S3, HL60, HepG2) or primary PBMCs for up to 10 μM. We report the first example of the PNP inhibitor exhibiting over 60-fold selectivity for the pathogenic enzyme (PNP) over hPNP. The results are supported by a crystallographic study of eight enzyme-inhibitor complexes and by ADMET profiling and .

PubMed: 37134237
DOI: 10.1021/acs.jmedchem.2c02097

Experimental method

X-RAY DIFFRACTION (1.97 Å)