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EBioMedicine Jun 2020The rapid development of nanotechnology results in the emergence of nanomedicines, but the effective delivery of drugs to tumor sites remains a great challenge.... (Review)
Review
The rapid development of nanotechnology results in the emergence of nanomedicines, but the effective delivery of drugs to tumor sites remains a great challenge. Prodrug-based cancer nanomedicines thus emerged due to their unique advantages, including high drug load efficiency, reduced side effects, efficient targeting, and real-time controllability. A distinctive characteristic of prodrug-based nanomedicines is that they need to be activated by a stimulus or multi-stimulus to produce an anti-tumor effect. A better understanding of various responsive approaches could allow researchers to perceive the mechanism of prodrug-based nanomedicines effectively and further optimize their design strategy. In this review, we highlight the stimuli-responsive pathway of prodrug-based nanomedicines and their anticancer applications. Furthermore, various types of prodrug-based nanomedicines, recent progress and prospects of stimuli-responsive prodrug-based nanomedicines and patient data in the clinical application are also summarized. Additionally, the current development and future challenges of prodrug-based nanomedicines are discussed. We expect that this review will be valuable for readers to gain a deeper understanding of the structure and development of prodrug-based cancer nanomedicines to design rational and effective drugs for clinical use.
Topics: Humans; Hydrogen-Ion Concentration; Nanoparticles; Neoplasms; Oxidative Stress; Prodrugs
PubMed: 32505922
DOI: 10.1016/j.ebiom.2020.102821 -
Nucleic Acids Research Jan 2022Drug discovery relies on the knowledge of not only drugs and targets, but also the comparative agents and targets. These include poor binders and non-binders for...
Drug discovery relies on the knowledge of not only drugs and targets, but also the comparative agents and targets. These include poor binders and non-binders for developing discovery tools, prodrugs for improved therapeutics, co-targets of therapeutic targets for multi-target strategies and off-target investigations, and the collective structure-activity and drug-likeness landscapes of enhanced drug feature. However, such valuable data are inadequately covered by the available databases. In this study, a major update of the Therapeutic Target Database, previously featured in NAR, was therefore introduced. This update includes (a) 34 861 poor binders and 12 683 non-binders of 1308 targets; (b) 534 prodrug-drug pairs for 121 targets; (c) 1127 co-targets of 672 targets regulated by 642 approved and 624 clinical trial drugs; (d) the collective structure-activity landscapes of 427 262 active agents of 1565 targets; (e) the profiles of drug-like properties of 33 598 agents of 1102 targets. Moreover, a variety of additional data and function are provided, which include the cross-links to the target structure in PDB and AlphaFold, 159 and 1658 newly emerged targets and drugs, and the advanced search function for multi-entry target sequences or drug structures. The database is accessible without login requirement at: https://idrblab.org/ttd/.
Topics: Databases, Factual; Drug Discovery; Humans; Molecular Targeted Therapy; Prodrugs; Structure-Activity Relationship
PubMed: 34718717
DOI: 10.1093/nar/gkab953 -
Science Advances Nov 20226-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8 T cells....
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8 T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl()-2-(()-2-acetamido-3-(1-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8 T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.
Topics: Humans; Prodrugs; Diazooxonorleucine; Glutamine; CD8-Positive T-Lymphocytes; Neoplasms; Enzyme Inhibitors
PubMed: 36383674
DOI: 10.1126/sciadv.abq5925 -
Chemical Society Reviews Oct 2017Covalent modification of therapeutic compounds is a clinically proven strategy to devise prodrugs with enhanced treatment efficacies. This prodrug strategy relies on the... (Review)
Review
Covalent modification of therapeutic compounds is a clinically proven strategy to devise prodrugs with enhanced treatment efficacies. This prodrug strategy relies on the modified drugs that possess advantageous pharmacokinetic properties and administration routes over their parent drug. Self-assembling prodrugs represent an emerging class of therapeutic agents capable of spontaneously associating into well-defined supramolecular nanostructures in aqueous solutions. The self-assembly of prodrugs expands the functional space of conventional prodrug design, affording a possible pathway to more effective therapies as the assembled nanostructure possesses distinct physicochemical properties and interaction potentials that can be tailored to specific administration routes and disease treatment. In this review, we will discuss the various types of self-assembling prodrugs in development, providing an overview of the methods used to control their structure and function and, ultimately, our perspective on their current and future potential.
Topics: Humans; Nanostructures; Prodrugs
PubMed: 29019492
DOI: 10.1039/c7cs00521k -
Molecular Therapy : the Journal of the... May 2021The inclusion of genes that control cell fate (so-called suicide, or kill-switch, genes) into gene therapy vectors is based on a compelling rationale for the safe and... (Review)
Review
The inclusion of genes that control cell fate (so-called suicide, or kill-switch, genes) into gene therapy vectors is based on a compelling rationale for the safe and selective elimination of aberrant transfected cells. Prodrug-activated systems were developed in the 1980s and 1990s and rely on the enzymatic conversion of non-active prodrugs to active metabolites that lead to cell death. Although considerable effort and ingenuity has gone into vector design for gene therapy, less attention has been directed at the efficacy or associated adverse effects of the prodrug systems employed. In this review, we discuss prodrug systems employed in clinical trials and consider their role in the field of gene therapy. We highlight potential drawbacks associated with the use of specific prodrugs, such as systemic toxicity of the activated compound, the paucity of data on biodistribution of prodrugs, bystander effects, and destruction of genetically modified cells, and how these can inform future advances in cell therapies.
Topics: Combined Modality Therapy; Genetic Therapy; Humans; Neoplasms; Prodrugs; Tissue Distribution
PubMed: 33831557
DOI: 10.1016/j.ymthe.2021.04.006 -
Biochimie Feb 2023Bacteria protect themselves from the toxicity of antimicrobial metabolites they produce through several strategies. In one resistance mechanism, bacteria assemble a... (Review)
Review
Bacteria protect themselves from the toxicity of antimicrobial metabolites they produce through several strategies. In one resistance mechanism, bacteria assemble a non-toxic precursor on an N-acyl-d-asparagine prodrug motif in the cytoplasm, then export it to the periplasm where a dedicated d-amino peptidase hydrolyzes the prodrug motif. These prodrug-activating peptidases contain an N-terminal periplasmic S12 hydrolase domain and C-terminal transmembrane domains (TMDs) of varying lengths: type I peptidases contain three transmembrane helices, and type II peptidases have an additional C-terminal ABC half-transporter. We review studies which have addressed the role of the TMD in function, the substrate specificity, and the biological assembly of ClbP, the type I peptidase that activates colibactin. We use modeling and sequence analyses to extend those insights to other prodrug-activating peptidases and ClbP-like proteins which are not part of prodrug resistance gene clusters. These ClbP-like proteins may play roles in the biosynthesis or degradation of other natural products, including antibiotics, may adopt different TMD folds, and have different substrate specificity compared to prodrug-activating homologs. Finally, we review the data supporting the long-standing hypothesis that ClbP interacts with transporters in the cell and that this association is important for the export of other natural products. Future investigations of this hypothesis as well as of the structure and function of type II peptidases will provide a complete account of the role of prodrug-activating peptidases in the activation and secretion of bacterial toxins.
Topics: Peptide Hydrolases; Prodrugs; Escherichia coli; Escherichia coli Proteins
PubMed: 36803695
DOI: 10.1016/j.biochi.2022.07.019 -
Biochemistry Jun 2018Covalent enzyme inhibitors are widely applied as biochemical tools and therapeutic agents. As a complement to categorization of these inhibitors by reactive group or... (Review)
Review
Covalent enzyme inhibitors are widely applied as biochemical tools and therapeutic agents. As a complement to categorization of these inhibitors by reactive group or modification site, we present a categorization by mechanism, which highlights common advantages and disadvantages inherent to each approach. Established categories for reversible and irreversible covalent inhibition are reviewed with representative examples given for each class, including covalent reversible inhibitors, slow substrates, residue-specific reagents, affinity labels (classical, quiescent, and photoaffinity), and mechanism-based inactivators. The relationships of these categories to proteomic profiling probes (activity-based and reactivity-based) as well as complementary approaches such as prodrug and soft drug design are also discussed. A wide variety of strategies are used to balance reactivity and selectivity in the design of covalent enzyme inhibitors. Use of a shared terminology is encouraged to clearly convey these mechanisms, to relate them to prior use of covalent inhibitors in enzymology, and to facilitate the development of more effective covalent inhibitors.
Topics: Humans; Molecular Structure; Prodrugs; Protein Kinase Inhibitors; Ribosomal Protein S6 Kinases, 90-kDa
PubMed: 29689165
DOI: 10.1021/acs.biochem.8b00315 -
European Journal of Pharmaceutics and... Aug 2021Extensive research into prodrug modification of active pharmaceutical ingredients and nanoparticle drug delivery systems has led to unprecedented levels of control over... (Review)
Review
Extensive research into prodrug modification of active pharmaceutical ingredients and nanoparticle drug delivery systems has led to unprecedented levels of control over the pharmacological properties of drugs and resulted in the approval of many prodrug or nanoparticle-based therapies. In recent years, the combination of these two strategies into prodrug-based nanoparticle drug delivery systems (PNDDS) has been explored as a way to further advance nanomedicine and identify novel therapies for difficult-to-treat indications. Many of the PNDDS currently in the clinical development pipeline are expected to enter the market in the coming years, making the rapidly evolving field of PNDDS highly relevant to pharmaceutical scientists. This review paper is intended to introduce PNDDS to the novice reader while also updating those working in the field with a comprehensive summary of recent efforts. To that end, first, an overview of FDA-approved prodrugs is provided to familiarize the reader with their advantages over traditional small molecule drugs and to describe the chemistries that can be used to create them. Because this article is part of a themed issue on nanoparticles, only a brief introduction to nanoparticle-based drug delivery systems is provided summarizing their successful application and unfulfilled opportunities. Finally, the review's centerpiece is a detailed discussion of rationally designed PNDDS formulations in development that successfully leverage the strengths of prodrug and nanoparticle approaches to yield highly effective therapeutic options for the treatment of many diseases.
Topics: Drug Carriers; Drug Development; Humans; Nanomedicine; Nanoparticles; Prodrugs
PubMed: 33979661
DOI: 10.1016/j.ejpb.2021.04.025 -
Advanced Science (Weinheim,... Sep 2021This article provides a broad spectrum about the nanoprodrug fabrication advances co-driven by prodrug and nanotechnology development to potentiate cancer treatment. The... (Review)
Review
This article provides a broad spectrum about the nanoprodrug fabrication advances co-driven by prodrug and nanotechnology development to potentiate cancer treatment. The nanoprodrug inherits the features of both prodrug concept and nanomedicine know-how, attempts to solve underexploited challenge in cancer treatment cooperatively. Prodrugs can release bioactive drugs on-demand at specific sites to reduce systemic toxicity, this is done by using the special properties of the tumor microenvironment, such as pH value, glutathione concentration, and specific overexpressed enzymes; or by using exogenous stimulation, such as light, heat, and ultrasound. The nanotechnology, manipulating the matter within nanoscale, has high relevance to certain biological conditions, and has been widely utilized in cancer therapy. Together, the marriage of prodrug strategy which shield the side effects of parent drug and nanotechnology with pinpoint delivery capability has conceived highly camouflaged Trojan horse to maneuver cancerous threats.
Topics: Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Prodrugs
PubMed: 34323373
DOI: 10.1002/advs.202101454 -
Molecules (Basel, Switzerland) Nov 2007Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for... (Review)
Review
Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter- and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990 s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.
Topics: Amides; Amines; Animals; Biological Availability; Cyclization; Drug Design; Humans; Molecular Structure; Peptides; Prodrugs
PubMed: 18065953
DOI: 10.3390/12112484