Nitroreductase gene-directed enzyme prodrug therapy: insights and advances toward clinical utility.

Biochem J

School of Biological Sciences, Victoria University of Wellington, Wellington 6140, New Zealand Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1023, New Zealand

Published: October 2015

This review examines the vast catalytic and therapeutic potential offered by type I (i.e. oxygen-insensitive) nitroreductase enzymes in partnership with nitroaromatic prodrugs, with particular focus on gene-directed enzyme prodrug therapy (GDEPT; a form of cancer gene therapy). Important first indications of this potential were demonstrated over 20 years ago, for the enzyme-prodrug pairing of Escherichia coli NfsB and CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide]. However, it has become apparent that both the enzyme and the prodrug in this prototypical pairing have limitations that have impeded their clinical progression. Recently, substantial advances have been made in the biodiscovery and engineering of superior nitroreductase variants, in particular development of elegant high-throughput screening capabilities to enable optimization of desirable activities via directed evolution. These advances in enzymology have been paralleled by advances in medicinal chemistry, leading to the development of second- and third-generation nitroaromatic prodrugs that offer substantial advantages over CB1954 for nitroreductase GDEPT, including greater dose-potency and enhanced ability of the activated metabolite(s) to exhibit a local bystander effect. In addition to forging substantial progress towards future clinical trials, this research is supporting other fields, most notably the development and improvement of targeted cellular ablation capabilities in small animal models, such as zebrafish, to enable cell-specific physiology or regeneration studies.

Download full-text PDF

Source
http://dx.doi.org/10.1042/BJ20150650DOI Listing

Publication Analysis

Top Keywords

enzyme prodrug
12
gene-directed enzyme
8
prodrug therapy
8
nitroaromatic prodrugs
8
nitroreductase
4
nitroreductase gene-directed
4
therapy insights
4
advances
4
insights advances
4
advances clinical
4

Similar Publications

Breaking the Myth of Enzymatic Azoreduction.

ACS Chem Biol

December 2024

Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, Maryland 21218, United States.

Flavin-dependent azoreductases have been applied to a wide range of tasks from decolorizing numerous azo dyes to releasing azo-conjugated prodrugs. A general narrative reiterated in much of the literature suggests that this enzyme promotes sequential reduction of both the azo-containing substrate and its corresponding hydrazo product to release the aryl amine components while consuming two equivalents of NAD(P)H. Indeed, such aryl amines can be formed by incubation of certain azo compounds with azoreductases, but the nature of the substrates capable of this apparent azo bond lysis remained unknown.

View Article and Find Full Text PDF

Advances in the Delivery, Activation and Therapeutics Applications of Bioorthogonal Prodrugs.

Med Res Rev

December 2024

Department of Medicinal Chemistry, Laboratory of Medicinal Chemical Biology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.

Traditional prodrug strategies have been leveraged to overcome many inherent drawbacks of active native drugs in the drug research and development. However, endogenous stimuli such as specific microenvironment or enzymes are relied on to achieve the prodrug activation, resulting in unintended drug release and systemic toxicity. Alternatively, bioorthogonal cleavage reaction-enabled bioorthogonal prodrugs activation via exogenous triggers has emerged as a valuable approach, featuring spatiotemporally controlled drug release.

View Article and Find Full Text PDF

Quantification of gimeracil, tegafur, and 5-FU in human plasma via LC-MS/MS with a simplified pretreatment using flow-through extraction.

J Chromatogr B Analyt Technol Biomed Life Sci

December 2024

Laboratory of Clinical Pharmacy and Sciences, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan. Electronic address:

Gimeracil, a component in S-1 (an oral anticancer agent comprising tegafur, a prodrug of 5-fluorouracil (5-FU), potassium oxonate, and gimeracil), inhibits metabolic enzymes, thereby impeding 5-FU degradation. Therefore, the blood level of gimeracil is closely associated with the disposition of 5-FU, and quantification of gimeracil can provide important information if a case shows an inappropriate 5-FU blood concentration. Nevertheless, methods for quantifying gimeracil in human plasma are rarely reported.

View Article and Find Full Text PDF

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX.

Elife

December 2024

Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.

We designed novel pre-drug compounds that transform into an active form that covalently modifies particular His residue in the active site, a difficult task to achieve, and applied to carbonic anhydrase (CAIX), a transmembrane protein, highly overexpressed in hypoxic solid tumors, important for cancer cell survival and proliferation because it acidifies tumor microenvironment helping invasion and metastases processes. The designed compounds have several functionalities: (1) primary sulfonamide group recognizing carbonic anhydrases (CA), (2) high-affinity moieties specifically recognizing CAIX among all CA isozymes, and (3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high initial affinity and selectivity for the disease target protein followed by complete irreversible inactivation of the protein via covalent modification.

View Article and Find Full Text PDF

This report describes the asymmetric synthesis of a focused library of enantiopure structured triacylglycerols (TAGs) comprised of a single saturated fatty acid (C6, C8, C10, C12, C14 or C16), a pure bioactive n-3 polyunsaturated fatty acid (EPA or DHA) and a potent drug (ibuprofen or naproxen) intended as a novel type of prodrug. One of the terminal -1 or -3 positions of the glycerol backbone is occupied with a saturated fatty, the remaining one with a PUFA, and the drug entity is present in the -2 position. This was accomplished by a six-step chemoenzymatic approach starting from enantiopure ()- and ()-solketals.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!