Editorial pubs.acs.org/molecularpharmaceutics
Solving the Prodrug Design and Activation Puzzle ometimes it seems that the field of prodrug development is similar to the popular numbers puzzle, Sudoku. For the uninitiated, Sudoku is a puzzle in which players insert the numbers one to nine into a grid consisting of nine squares subdivided into a further nine smaller squares in such a way that every number appears once in each horizontal line, vertical line, and square. Typically, there comes a time when solving these puzzles that insertion of one number at the appropriate spot will turn on the light bulb, so to speak, and the solution for the remaining portion of the puzzle falls into place. The degree of difficulty of the puzzle is determined by how many numbers are given at the start; fewer numbers means greater difficulty. Let us be clear, prodrug design has a much greater degree of difficulty than the average puzzle, but as illustrated by the articles contained in this featured topic issue of Molecular Pharmaceutics titled “Prodrug Design and Target Site Activation”, finding the right structure that fits into the appropriate spot can yield very productive prodrug solutions to the drug discovery and development puzzle. For starters, work on cyclic phosphate prodrugs of 5-ASA by Huttunen and co-workers demonstrates that a delicate balance between chemical stability and CYP3a activation can be struck with the proper placement of a chlorine residue in the aromatic ring of the promoiety. Gupta et al. illustrate that a simple methyl group added to the promoiety structure for a neuraminidase inhibitor can significantly improve the prodrug’s chemical stability and its membrane permeability through interaction with HPEPT1, the human dipeptide transporter. HPEPT1 has long been known to act as a portal for drug delivery in the intestine. Indeed, the approved drug valacylovir, the amino acid ester prodrug of acyclovir, has been shown to use this transporter to gain systemic entry into the body. Tai et al. detail studies that may extend the potential usefulness of this transporter as a drug delivery portal in their work on expression of peptide transporters in pancreatic tumor cells. Prodrugs of the anticancer agent gemcitabine are the focus of the review by Bastiat et al., specifically modifications around the 5′ and 4-(N) position that can stabilize the drug against chemical and metabolic inactivation while overcoming mechanisms of resistance prevalent with the parent compound. In work on prodrugs of the anti-HIV drug emtricitabine, Agarwal et al. describe their work on fatty acyl prodrugs that show marked increase in antiviral activity and a better resistance profile than the parent compound. Using a phosphoramidate prodrug approach, Babusis and co-workers detail the improvement of absorption and stability of a tenofovir prodrug that results in near complete absorption and effective loading of the activated drug in the lymphoid target cells. Continuing in the phosphoramidate vein, Li and co-workers detail their findings on a tryptamine phosphoramidate prodrug of a potent antagonist of eIF4E cap binding that sensitizes breast and lung cells to nontoxic levels of gemcitabine. And, following a slightly different tack, Krylov et al. review their work on antiviral amino acid prodrugs of nucleoside phosphonates that significantly enhance the cellular permeability and antiviral
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© 2013 American Chemical Society
activity of the parent nucleoside phosphonate. The aforementioned investigations detail efforts in what may be considered traditional prodrug solutions to the drug development puzzle. However, significant inroads in more innovative prodrug work are described in three additional articles of this special edition. In a pair of articles, Shirazi and co-workers provide detailed studies on the utility of cyclic peptides, both covalently attached and noncovalent capped gold nanoparticles as prodrugs for delivery of both antiviral and anticancer agents. Finally, Goswami et al. describe their efforts on optimizing a chemical antibody directed against α5β1 integrin with potential use as a therapeutic or diagnostic tool. These articles detail the authors’ trials and tribulations in using prodrugs as a means to solve the drug development puzzle. As you read these articles, here is to hoping that the light bulb goes on for you!
John Hilfinger, Guest Editor
TSRL Inc., Ann Arbor, Michigan 48108, United States
Special Issue: Prodrug Design and Target Site Activation Published: February 4, 2013 429
dx.doi.org/10.1021/mp4000025 | Mol. Pharmaceutics 2013, 10, 429−429
