Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • News & Views
  • Published:

PHARMACOTHERAPY

Small-molecule inhibitors get pro-inflammatory TNF into shape

Newly discovered small-molecule TNF inhibitors serve as antagonists of pro-inflammatory TNF signalling by uniquely harnessing the conformational plasticity of trimeric TNF. The development of this approach could mark a resurgence of non-biologic modulators of clinically relevant protein–protein interactions in rheumatology.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanisms of action of TNF inhibitors.

References

  1. Kalliolias, G. D. & Ivashkiv, L. B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 12, 49–62 (2016).

    Article  CAS  Google Scholar 

  2. Steeland, S., Libert, C. & Vandenbroucke, R. E. A new venue of TNF targeting. Int. J. Mol. Sci. 19, 1442 (2018).

    Article  Google Scholar 

  3. Jairath, V. & Feagan, B. G. Global burden of inflammatory bowel disease. Lancet Gastroenterol. Hepatol. 5, 2–3 (2020).

    Article  Google Scholar 

  4. O’Connell, J. et al. Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer. Nat. Commun. 10, 5795 (2019).

    Article  Google Scholar 

  5. Scott, D. E., Bayly, A. R., Abell, C. & Skidmore, J. Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat. Rev. Drug Discov. 15, 533–550 (2016).

    Article  CAS  Google Scholar 

  6. He, M. M. et al. Small-molecule inhibition of TNF-alpha. Science 310, 1022–1025 (2005).

    Article  CAS  Google Scholar 

  7. Davis, J. M. & Colangelo, J. Small-molecule inhibitors of the interaction between TNF and TNFR. Future Med. Chem. 5, 69–79 (2013).

    Article  CAS  Google Scholar 

  8. Mak, K. K. & Pichika, M. R. Artificial intelligence in drug development: present status and future prospects. Drug Discov. Today 24, 773–780 (2019).

    Article  Google Scholar 

  9. Nair, N. & Wilson, A. G. Can machine learning predict responses to TNF inhibitors? Nat. Rev. Rheumatol. 15, 702–704 (2019).

    Article  Google Scholar 

  10. Kingsmore, K. M., Grammer, A. C. & Lipsky, P. E. Drug repurposing to improve treatment of rheumatic autoimmune inflammatory diseases. Nat. Rev. Rheumatol. 16, 32–52 (2020).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

S.N.S. is supported by grants from Research Foundation Flanders-Belgium (FWO), Ghent University and VIB, Belgium. D.E. acknowledges support from FWO and VIB.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Savvas N. Savvides.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Savvides, S.N., Elewaut, D. Small-molecule inhibitors get pro-inflammatory TNF into shape. Nat Rev Rheumatol 16, 189–190 (2020). https://doi.org/10.1038/s41584-020-0388-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-020-0388-2

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research