First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity

Wai Soon Eng; Dana Hocková; Petr Špaček; Zlatko Janeba; Nicholas P West; Kyra Woods; Lieve M J Naesens; Dianne T Keough; Luke W Guddat

doi:10.1021/acs.jmedchem.5b00611

First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity

J Med Chem. 2015 Jun 11;58(11):4822-38. doi: 10.1021/acs.jmedchem.5b00611. Epub 2015 May 13.

Authors

Wai Soon Eng¹, Dana Hocková², Petr Špaček², Zlatko Janeba², Nicholas P West¹, Kyra Woods¹, Lieve M J Naesens³, Dianne T Keough¹, Luke W Guddat¹

Affiliations

¹ †The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD Australia.
² ‡Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic.
³ §Rega Institute for Medical Research, KU Leuven - University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.

PMID: 25915781
DOI: 10.1021/acs.jmedchem.5b00611

Abstract

Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 μM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 μM and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 μM). In addition, the first crystal structures of MtHGPRT (2.03-2.76 Å resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Catalytic Domain
Cell Proliferation / drug effects
Crystallography, X-Ray
Diphosphates / chemistry
Diphosphates / metabolism*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Guanosine Monophosphate / chemistry
Guanosine Monophosphate / metabolism*
Humans
Hypoxanthine Phosphoribosyltransferase / chemistry
Hypoxanthine Phosphoribosyltransferase / metabolism*
Lung Neoplasms / drug therapy
Lung Neoplasms / pathology
Models, Molecular
Molecular Sequence Data
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Organophosphonates / chemistry
Organophosphonates / metabolism*
Prodrugs / chemistry
Prodrugs / pharmacology*
Protein Conformation
Sequence Homology, Amino Acid
Structure-Activity Relationship
Tuberculosis / drug therapy*
Tuberculosis / microbiology
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Antitubercular Agents
Diphosphates
Enzyme Inhibitors
Organophosphonates
Prodrugs
diphosphoric acid
Guanosine Monophosphate
Hypoxanthine Phosphoribosyltransferase