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Advances in TRP channel drug discovery: from target validation to clinical studies

Nature Reviews Drug Discovery volume 21, pages 41–59 (2022)Cite this article

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Abstract

Transient receptor potential (TRP) channels are multifunctional signalling molecules with many roles in sensory perception and cellular physiology. Therefore, it is not surprising that TRP channels have been implicated in numerous diseases, including hereditary disorders caused by defects in genes encoding TRP channels (TRP channelopathies). Most TRP channels are located at the cell surface, which makes them generally accessible drug targets. Early drug discovery efforts to target TRP channels focused on pain, but as our knowledge of TRP channels and their role in health and disease has grown, these efforts have expanded into new clinical indications, ranging from respiratory disorders through neurological and psychiatric diseases to diabetes and cancer. In this Review, we discuss recent findings in TRP channel structural biology that can affect both drug development and clinical indications. We also discuss the clinical promise of novel TRP channel modulators, aimed at both established and emerging targets. Last, we address the challenges that these compounds may face in clinical practice, including the need for carefully targeted approaches to minimize potential side-effects due to the multifunctional roles of TRP channels.

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Fig. 1: Similarities and differences between the structures of TRP channels.
Fig. 2: TRPV1 in the pain pathway: similarities and differences between desensitization by agonists and blockade by antagonists.
Fig. 3: Structural information on ligand and drug binding by TRP channels, and gain-of-function mutations.
Fig. 4: The pain pathway: wide expression of TRP channels in sensory neurons, skin and brain.

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Acknowledgements

We thank N. Gavva (Takeda Pharma) for useful comments. This work was funded in part by NIH grant 1R21DC018497 (to R.G.).

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Authors and Affiliations

  1. R&D, Neurological Disorders Research, Orion Pharma, Turku, Finland

    Ari-Pekka Koivisto

  2. Research & Early Development, Respiratory & Immunology BioPharmaceuticals-R&D, AstraZeneca, Gothenburg, Sweden

    Maria G. Belvisi

  3. Respiratory Pharmacology Group, Airway Disease, National Heart & Lung Institute, Imperial College London, London, UK

    Maria G. Belvisi

  4. Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA

    Rachelle Gaudet

  5. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

    Arpad Szallasi

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  1. Ari-Pekka Koivisto
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  3. Rachelle Gaudet
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  4. Arpad Szallasi
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All authors wrote the article. A.S. outlined the content and reviewed and edited the manuscript before submission.

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Correspondence to Arpad Szallasi.

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Koivisto, AP., Belvisi, M.G., Gaudet, R. et al. Advances in TRP channel drug discovery: from target validation to clinical studies. Nat Rev Drug Discov 21, 41–59 (2022). https://doi.org/10.1038/s41573-021-00268-4

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