Special Issue "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).

Special Issue Editors

Prof. Dr. Barbara R. Conway
E-Mail Website
Guest Editor
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
Dr. Milica Markovic
E-Mail Website
Guest Editor
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 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

Manuscript Submission Information

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

Published Papers (1 paper)

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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
Viewed by 430
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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