Prospects of the Prodrug Approach: From Initial Design to Clinical Application

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 8693

Special Issue Editors

Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK
Interests: biopharmaceutics; modified release; dissolution; infection prevention; biopolymers
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA
Interests: prodrugs; drug delivery; drug targeting; oral drug absorption; biopharmaceutics; intestinal permeability; neuropharmacology; Parkinson’s disease; inflammatory bowel disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Prodrugs are an increasingly used tool for overcoming physicochemical, biopharmaceutical, pharmacokinetic, and pharmacodynamic obstacles of pharmacologically active agents. To date, it is estimated that 10% of drugs in the market are classified as prodrugs; among low-molecular-weight drugs, one third are categorized as prodrugs. The increased utilization of prodrug strategies in drug development results from an increased understanding of the biological mechanisms, enabling the smart design of prodrugs with better biopharmaceutical and safety profiles. Even though smart prodrug design is challenging, it can be faster, more practical, and more efficacious than other formulation approaches and is certainly preferable in most cases to going back to the drawing board to search for an entirely new compound. When considered at the early stages of preclinical development, the prodrug approach may save time, protect resources, and facilitate the overall drug development process. This Special Issue serves to present and highlight the most recent examples and future uses of the prodrug approach from its initial design to the clinical setting.   

Prof. Dr. Barbara R. Conway
Dr. Milica Markovic
Guest Editors

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Keywords

  • prodrugs
  • prodrug design
  • bioconversion
  • enzyme-mediated prodrug activation
  • drug targeting
  • drug delivery
  • clinical prodrug use
  • oral bioavailability
  • ProTide

Published Papers (3 papers)

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Research

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12 pages, 8836 KiB  
Article
PLA2-Triggered Activation of Cyclosporine-Phospholipid Prodrug as a Drug Targeting Approach in Inflammatory Bowel Disease Therapy
Pharmaceutics 2022, 14(3), 675; https://doi.org/10.3390/pharmaceutics14030675 - 18 Mar 2022
Cited by 5 | Viewed by 2331
Abstract
Oral medication with activity specifically at the inflamed sites throughout the gastrointestinal tract and limited systemic exposure would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). For this purpose, we have designed a prodrug by linking active drug [...] Read more.
Oral medication with activity specifically at the inflamed sites throughout the gastrointestinal tract and limited systemic exposure would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). For this purpose, we have designed a prodrug by linking active drug moiety to phospholipid (PL), the substrate of phospholipase A2 (PLA2). PLA2 expression and activity is significantly elevated in the inflamed intestinal tissues of IBD patients. Since PLA2 enzyme specifically hydrolyses the sn-2 bond within PLs, in our PL-based prodrug approach, the sn-2 positioned FA is replaced with cyclosporine, so that PLA2 may be exploited as the prodrug-activating enzyme, releasing the free drug from the PL-complex. Owing to the enzyme overexpression, this may effectively target free cyclosporine to the sites of inflammation. Four PL-cyclosporine prodrugs were synthesized, differing by their linker length between the PL and the drug moiety. To study the prodrug activation, a novel enzymatically enriched model was developed, the colonic brush border membrane vesicles (cBBMVs); in this model, tissue vesicles were produced from colitis-induced (vs. healthy) rat colons. PLA2 overexpression (3.4-fold) was demonstrated in diseased vs. healthy cBBMVs. Indeed, while healthy cBBMVs induced only marginal activation, substantial prodrug activation was evident by colitis-derived cBBMVs. Together with the PLA2 overexpression, these data validate our drug targeting strategy. In the diseased cBBMVs, quick and complete activation of the entire dose was obtained for the 12-carbon linker prodrug, while slow and marginal activation was obtained for the 6/8-carbon linkers. The potential to target the actual sites of inflammation and treat any localizations throughout the GIT, together with the extended therapeutic index, makes this orally delivered prodrug approach an exciting new therapeutic strategy for IBD treatment. Full article
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15 pages, 2137 KiB  
Article
Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection
Pharmaceutics 2021, 13(10), 1656; https://doi.org/10.3390/pharmaceutics13101656 - 11 Oct 2021
Cited by 7 | Viewed by 2156
Abstract
ProTide technology is a powerful tool for the design of nucleoside/nucleotide analog prodrugs. ProTide prodrug design improves cell permeability and enhances intracellular activation. The hydrolysis of the ester bond of a ProTide is a determinant of the intracellular activation efficiency and final antiviral [...] Read more.
ProTide technology is a powerful tool for the design of nucleoside/nucleotide analog prodrugs. ProTide prodrug design improves cell permeability and enhances intracellular activation. The hydrolysis of the ester bond of a ProTide is a determinant of the intracellular activation efficiency and final antiviral efficacy of the prodrug. The hydrolysis is dictated by the catalytic activity and abundance of activating enzymes. The antiviral agents tenofovir alafenamide (TAF) and sofosbuvir (SBV) are typical ProTides. Both TAF and SBV have also been proposed to treat patients with COVID-19. However, the mechanisms underlying the activation of the two prodrugs in the lung remain inconclusive. In the present study, we profiled the catalytic activity of serine hydrolases in human lung S9 fractions using an activity-based protein profiling assay. We evaluated the hydrolysis of TAF and SBV using human lung and liver S9 fractions and purified enzymes. The results showed that CatA and CES1 were involved in the hydrolysis of the two prodrugs in the human lung. More specifically, CatA exhibited a nearly 4-fold higher hydrolytic activity towards TAF than SBV, whereas the CES1 activity on hydrolyzing TAF was slightly lower than that for SBV. Overall, TAF had a nearly 4-fold higher hydrolysis rate in human lung S9 than SBV. We further analyzed protein expression levels of CatA and CES1 in the human lung, liver, and primary cells of the two tissues using proteomics data extracted from the literature. The relative protein abundance of CatA to CES1 was considerably higher in the human lung and primary human airway epithelial cells than in the human liver and primary human hepatocytes. The findings demonstrated that the high susceptivity of TAF to CatA-mediated hydrolysis resulted in efficient TAF hydrolysis in the human lung, suggesting that CatA could be utilized as a target activating enzyme when designing antiviral ester prodrugs for the treatment of respiratory virus infection. Full article
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Review

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23 pages, 8669 KiB  
Review
Prodrug Therapies for Infectious and Neurodegenerative Diseases
Pharmaceutics 2022, 14(3), 518; https://doi.org/10.3390/pharmaceutics14030518 - 26 Feb 2022
Cited by 3 | Viewed by 3408
Abstract
Prodrugs are bioreversible drug derivatives which are metabolized into a pharmacologically active drug following chemical or enzymatic modification. This approach is designed to overcome several obstacles that are faced by the parent drug in physiological conditions that include rapid drug metabolism, poor solubility, [...] Read more.
Prodrugs are bioreversible drug derivatives which are metabolized into a pharmacologically active drug following chemical or enzymatic modification. This approach is designed to overcome several obstacles that are faced by the parent drug in physiological conditions that include rapid drug metabolism, poor solubility, permeability, and suboptimal pharmacokinetic and pharmacodynamic profiles. These suboptimal physicochemical features can lead to rapid drug elimination, systemic toxicities, and limited drug-targeting to disease-affected tissue. Improving upon these properties can be accomplished by a prodrug design that includes the careful choosing of the promoiety, the linker, the prodrug synthesis, and targeting decorations. We now provide an overview of recent developments and applications of prodrugs for treating neurodegenerative, inflammatory, and infectious diseases. Disease interplay reflects that microbial infections and consequent inflammation affects neurodegenerative diseases and vice versa, independent of aging. Given the high prevalence, personal, social, and economic burden of both infectious and neurodegenerative disorders, therapeutic improvements are immediately needed. Prodrugs are an important, and might be said a critical tool, in providing an avenue for effective drug therapy. Full article
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