TNFR superfamily trimers | Nature Reviews Drug Discovery

Access through your institution Buy or subscribe The TNFR superfamily includes receptors such as CD40, lymphotoxin receptor and nerve growth factor receptor. These receptors are involved in

a wide range of diseases from inflammatory conditions to cancer. Inhibition of TNFα by the biologics etanercept (Enbrel; Amgen), infliximab (Remicade; Centocor/Schering-Plough) and

adalimumab (Humira; Abbott) for the treatment of rheumatoid arthritis has established itself as an effective therapeutic strategy, and has validated the targeting of this pathway. Current

strategies for the development of small-molecule antagonists of TNFα and its signalling pathway include inhibiting TNF-converting enzyme or other upstream signal transduction molecules such

as nuclear factor-κB. However, developing functional small-molecule agonists and antagonists of these receptors is challenging because of the requirement to disrupt protein–protein

interactions as well as integrating the correct three-fold symmetry. Guichard and colleagues designed small synthetic molecules with three-fold symmetry that can mimic CD40 ligand (CD40L)

homotrimers. The molecular scaffold incorporated a circular core with three arms, at twelve, four and eight o'clock positions. To each arm, they attached a short peptide derived from

CD40L that is known to interact with CD40. The geometry and distances of the C3 molecule could match those of the CD40L homotrimer and bind to and activate CD40. The authors demonstrated

that the molecules mimic the action of CD40L by signalling through CD40 in B lymphoma cells and dendritic cells. Furthermore, the molecules targeted only CD40 and did not activate other TNF

receptor proteins. This specificity suggests that these C3 molecular cores could be a versatile platform for targeting different TNFRs by decorating them with the appropriate peptide

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are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support ORIGINAL RESEARCH PAPER * Fournel, S.

et al. C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L. _Nature Chem. Biol._ 10.1038/nchembio746 (2005) * He, M. M. et al. Small-molecule inhibition of TNF-α.

_Science_ 310, 1022–1025 (2005) Article  CAS  Google Scholar  Download references Authors * Melanie Brazil View author publications You can also search for this author inPubMed Google

Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Brazil, M. TNFR superfamily trimers. _Nat Rev Drug Discov_ 5, 20 (2006).

https://doi.org/10.1038/nrd1952 Download citation * Issue Date: 01 January 2006 * DOI: https://doi.org/10.1038/nrd1952 SHARE THIS ARTICLE Anyone you share the following link with will be

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