Prodrugs are pharmacologically inactive compounds that undergo enzymatic or chemical transformation in vivo to release active drugs. This strategy has emerged as a powerful tool in modern drug development, addressing key limitations such as poor solubility, limited bioavailability, rapid metabolism, and systemic toxicity. This review provides a comprehensive overview of prodrug classifications, including carrier-linked, bio-precursor, and self-immolative systems, and their applications across therapeutic areas such as oncology, infectious diseases, and cardiovascular disorders. It explores historical developments, rational design strategies (e.g., mutual, co-drugs, double prodrugs), and molecular targeting approaches including enzyme-, pH, and redox-sensitive systems. Additionally, it discusses macromolecular and nanoparticle-based prodrugs and evaluates key challenges in stability, activation variability, and toxicity from released promoieties. Emphasis is also placed on emerging trends such as biorthogonal activation, probiologics, and machine learning-guided design. By integrating advances in nanotechnology, precision medicine, and computational modeling, prodrugs are poised to transform therapeutic delivery in increasingly targeted and patient-specific ways.
References
[1]
Mallhi, T.H., Butt, M.H., Ahmad, A., Misbah, S., Salman, M., Khan, A., et al. (2022) Drug-Metabolizing Enzymes and Fate of Prodrugs: From Function to Regulation. Biochemistry of Drug Metabolizing Enzymes, 125-139. https://doi.org/10.1016/B978-0-323-95120-3.00005-1
[2]
Choudhury, C., Kumar, V. and Kumar, R. (2023) SmProdrugs: A Repository of Small Molecule Prodrugs. European Journal of Medicinal Chemistry, 249, Article 115153. https://doi.org/10.1016/j.ejmech.2023.115153
[3]
Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., et al. (2008) Prodrugs: Design and Clinical Applications. Nature Reviews Drug Discovery, 7, 255-270. https://doi.org/10.1038/nrd2468
[4]
Markovic, M., Ben-Shabat, S. and Dahan, A. (2020) Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products. Pharmaceutics, 12, Article 1031. https://doi.org/10.3390/pharmaceutics12111031
[5]
Nasibullin, I., Smirnov, I., Ahmadi, P., Vong, K., Kurbangalieva, A. and Tanaka, K. (2022) Synthetic Prodrug Design Enables Biocatalytic Activation in Mice to Elicit Tumor Growth Suppression. Nature Communications, 13, Article No. 39. https://doi.org/10.1038/s41467-021-27804-5
[6]
Riley, T.N. (1988) The Prodrug Concept and New Drug Design and Development. Journal of Chemical Education, 65, 947. https://doi.org/10.1021/ed065p947
[7]
Abet, V., Filace, F., Recio, J., Alvarez-Builla, J. and Burgos, C. (2017) Prodrug Approach: An Overview of Recent Cases. European Journal of Medicinal Chemistry, 127, 810-827. https://doi.org/10.1016/j.ejmech.2016.10.061
[8]
Shah, K., Gupta, J.K., Chauhan, N.S., Upmanyu, N., Shrivastava, S.K. and Mishra, P. (2017) Prodrugs of Nsaids: A Review. The Open Medicinal Chemistry Journal, 11, 146-195. https://doi.org/10.2174/1874104501711010146
[9]
Carl, P.L., Chakravarty, P.K. and Katzenellenbogen, J.A. (1981) A Novel Connector Linkage Applicable in Prodrug Design. Journal of Medicinal Chemistry, 24, 479-480. https://doi.org/10.1021/jm00137a001
[10]
Matson, J., Dillon, K. and Powell, C. (2019) Self-Immolative Prodrugs: Effective Tools for the Controlled Release of Sulfur Signaling Species. Synlett, 30, 525-531. https://doi.org/10.1055/s-0037-1611693
[11]
Wu, K.-M. (2009) A New Classification of Prodrugs: Regulatory Perspectives. Pharmaceuticals, 2, 77-81. https://doi.org/10.3390/ph2030077
[12]
Jornada, D., Dos Santos Fernandes, G., Chiba, D., De Melo, T., Dos Santos, J. and Chung, M. (2015) The Prodrug Approach: A Successful Tool for Improving Drug Solubility. Molecules, 21, Article 42. https://doi.org/10.3390/molecules21010042
[13]
Ratnatilaka Na Bhuket, P., El-Magboub, A., Haworth, I.S. and Rojsitthisak, P. (2017) Enhancement of Curcumin Bioavailability via the Prodrug Approach: Challenges and Prospects. European Journal of Drug Metabolism and Pharmacokinetics, 42, 341-353. https://doi.org/10.1007/s13318-016-0377-7
[14]
Gupta, D., Gupta, S.V., Lee, K. and Amidon, G.L. (2009) Chemical and Enzymatic Stability of Amino Acid Prodrugs Containing Methoxy, Ethoxy and Propylene Glycol Linkers. Molecular Pharmaceutics, 6, 1604-1611. https://doi.org/10.1021/mp900084v
[15]
Zhou, G. (2024) Exploring Ester Prodrugs: A Comprehensive Review of Approaches, Applications, and Methods. Pharmacology & Pharmacy, 15, 269-284. https://doi.org/10.4236/pp.2024.158016
[16]
Huttunen, K.M., Raunio, H. and Rautio, J. (2011) Prodrugs—From Serendipity to Rational Design. Pharmacological Reviews, 63, 750-771. https://doi.org/10.1124/pr.110.003459
[17]
Dhaneshwar, S., Bhosle, D., Bharambe, S. and Gairola, N. (2006) Mutual Prodrug Concept: Fundamentals and Applications. Indian Journal of Pharmaceutical Sciences, 68, 286. https://doi.org/10.4103/0250-474x.26654
[18]
Das, N., Dhanawat, M., Dash, B., Nagarwal, R.C. and Shrivastava, S.K. (2010) Codrug: An Efficient Approach for Drug Optimization. European Journal of Pharmaceutical Sciences, 41, 571-588. https://doi.org/10.1016/j.ejps.2010.09.014
[19]
Ganesh R. Kokil, G. and V. Rewatkar, P. (2010) Bioprecursor Prodrugs: Molecular Modification of the Active Principle. Mini-Reviews in Medicinal Chemistry, 10, 1316-1330. https://doi.org/10.2174/138955710793564179
[20]
Bundgaard, H. (1989) The Double Prodrug Concept and Its Applications. Advanced Drug Delivery Reviews, 3, 39-65. https://doi.org/10.1016/0169-409x(89)90004-5
[21]
Han, H.-K. and Amidon, G.L. (2000) Targeted Prodrug Design to Optimize Drug Delivery. AAPS PharmSci, 2, 48-58. https://doi.org/10.1208/ps020106
[22]
Riber, C.F. and Zelikin, A.N. (2017) Recent Advances in Macromolecular Prodrugs. Current Opinion in Colloid & Interface Science, 31, 1-9. https://doi.org/10.1016/j.cocis.2017.06.002
[23]
Lagorce, D., Bouslama, L., Becot, J., Miteva, M.A. and Villoutreix, B.O. (2019) Predicting Blood-Brain Barrier Permeation Using Machine Learning: From Classical Algorithms to Deep Neural Networks. Journal of Chemical Information and Modeling, 59, 3286-3301.
