Signalling through receptors of the tumour-necrosis factor receptor (TNFR) superfamily requires the formation of trimeric ligand complexes that activate receptor chains and downstream events. The structures of several TNF family members in complex with their cognate receptors reveal that each trimeric ligand complex interacts with three monomeric receptor chains. Papers published in Nature Chemical Biology and Science describe a new approach to targeting TNFR pathways using small molecules to agonize and antagonize members of the TNFR superfamily, respectively.

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 fragments.

Cunningham and colleagues identified a small-molecule inhibitor of TNFα that promotes disassembly of the TNFα trimeric complex, and it is able to inhibit TNFα activity in biochemical and HeLa cell-based assays. The compound is composed of trifluoromethylphenyl indole and dimethyl chromone moieties linked by a spacer. X-ray crystallography revealed that the single-compound molecule displaces a subunit of the TNFα trimer to form a complex with a TNFα dimer. The authors considered how the compound acts to cause formation of the dimer; experimental evidence suggests that the compound actively interacts with the trimer to form an intermediate complex that undergoes accelerated subunit dissociation. This work suggests that small molecules can disrupt tightly pre-associated oligomeric proteins.