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Antioxidants & Redox Signaling Nov 2020This Forum was conceived as a means to usher in the age of HS-based therapeutics and HS-aided regenerative medicine. HS prodrugs-now in advanced stages of pharmaceutical...
This Forum was conceived as a means to usher in the age of HS-based therapeutics and HS-aided regenerative medicine. HS prodrugs-now in advanced stages of pharmaceutical development-will soon be available for treatment of a remarkably wide range of serious health conditions with minimal side effects/adverse reactions. Also foreseeable is the advent of a time in which the "one drug-one target" paradigm will be phased out, whereas multitargeted HS prodrugs find expanding roles in the treatment of highly complex disease states-such paradigm change will prevent polypharmacy and bring about truly disease-modifying outcomes. In the seven articles comprising Parts A and B of this Forum (2-4, 6-9), international experts survey remarkably diverse landscapes of small and large HS donor molecules, HS release profiles and mechanisms, pharmacophores/metabolic routes, and potential therapeutic or prophylactic indications. Donors of related sulfur species, such as persufides, SO, carbon oxysulfide (COS), and carbon disulfide, are examined as well. This Editorial highlights a few of the insights shared by the 32 Forum contributors and includes a proposed classification of HS/COS prodrugs that is intended to aid in the systematization of this burgeoning field.
Topics: Drug Development; Humans; Hydrogen Sulfide; Prodrugs
PubMed: 32689816
DOI: 10.1089/ars.2020.8078 -
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 -
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 -
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 -
Nature Reviews. Drug Discovery May 2024Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration... (Review)
Review
Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration to generate the API in situ. Although sharing this general characteristic, prodrugs encompass a wide range of different chemical structures, therapeutic indications and properties. Here we provide the first holistic analysis of the current landscape of approved prodrugs using cheminformatics and data science approaches to reveal trends in prodrug development. We highlight rationales that underlie prodrug design, their indications, mechanisms of API release, the chemistry of promoieties added to APIs to form prodrugs and the market impact of prodrugs. On the basis of this analysis, we discuss strengths and limitations of current prodrug approaches and suggest areas for future development.
Topics: Prodrugs; Humans; Animals; Drug Design; Drug Development
PubMed: 38565913
DOI: 10.1038/s41573-024-00914-7 -
Advanced Drug Delivery Reviews Sep 2017
Topics: Animals; Enzyme Therapy; Enzymes; Humans; Prodrugs
PubMed: 29054356
DOI: 10.1016/j.addr.2017.10.006 -
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 -
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 -
Drug Discovery Today Mar 2017The term 'prodrug' was first introduced by Albert in 1958. Generally, prodrugs can be utilized for improving active drug solubility and bioavailability, increasing drug... (Review)
Review
The term 'prodrug' was first introduced by Albert in 1958. Generally, prodrugs can be utilized for improving active drug solubility and bioavailability, increasing drug permeability and absorption, modifying the distribution profile, preventing fast metabolism and excretion, and reducing toxicity. Previously, the prodrug approach was a final resort during the drug discovery process only after all other approaches had been exhausted. However, this strategy is now considered during the early stages of the drug development process. Most antitubercular agents are defined as 'prodrugs', including isoniazid and ethionamide. Thus, the prodrug approach could provide novel targets for the rational design of more effective treatments for tuberculosis (TB).
Topics: Animals; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Prodrugs; Tuberculosis
PubMed: 27649942
DOI: 10.1016/j.drudis.2016.09.006 -
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