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The landscape of small-molecule prodrugs

Nature Reviews Drug Discovery (2024)Cite this article

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Abstract

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.

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Fig. 1: Prodrug structures and purposes.
Fig. 2: Characterization of currently approved prodrugs.
Fig. 3: Examples of prodrugs that have had a substantial market impact.
Fig. 4: Physicochemical properties of currently approved prodrugs.

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Acknowledgements

Z.F. is supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate (NDSEG) Fellowship Program. P.Z. acknowledges the support of NIAID grants AI139216 and AI152896. D.R. acknowledges the support of NIGMS grant R35GM151255.

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  1. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Zachary Fralish & Daniel Reker

  2. Department of Computer Science, Duke University, Durham, NC, USA

    Ashley Chen

  3. Rivus Pharmaceuticals, Charlottesville, VA, USA

    Shaharyar Khan

  4. Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA

    Pei Zhou

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Correspondence to Daniel Reker.

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D.R. acts as a consultant to the pharmaceutical and biotechnology industry, as a mentor for Start2, and serves on the scientific advisory board of Areteia Therapeutics. S.K. is Chief Scientific Officer at Rivus. P.Z. is a scientific co-founder of Valanbio Therapeutics aiming at developing novel antibiotics.

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Fralish, Z., Chen, A., Khan, S. et al. The landscape of small-molecule prodrugs. Nat Rev Drug Discov (2024). https://doi.org/10.1038/s41573-024-00914-7

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  • DOI: https://doi.org/10.1038/s41573-024-00914-7

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