A new approach to targeting cellular receptors in the immune system using small molecules is reported in the December issue of Nature Chemical Biology.
Gilles Guichard and colleagues designed a molecular scaffold that presents short peptide sequences that bind to and activate cellular receptors. These molecules offer an attractive model for cancer immunotherapy and boosting immune responses to infections.
Tumor necrosis factor (TNF) proteins are a family of cytokine proteins that regulate the functions of immune cells. TNF proteins assemble into bundles of three -- or trimeric bundles -- and bind to TNF receptors, which 'read' cytokine signals on the surface of immune cells. The team set out to create small molecules that could mimic the cytokine properties of trimeric CD40 ligand (CD40L), which exerts its effects by binding to trimeric CD40 receptors. The authors synthesized a circular 'core' peptide with three appendages, at twelve, four and eight o'clock. To each appendage, they attached a short peptide derived from CD40L that is known to interact with CD40. They showed that these trimeric molecules act as mimics of CD40L by binding to CD40 on cells and activating downstream signaling pathways. In addition, the molecules targeted only CD40 and did not activate other TNF receptor proteins. This specificity suggests that these molecular 'cores' may be a versatile platform for targeting different TNF receptors by decorating them with different TNF peptide fragments.
These molecules suggest new strategies for cancer immunotherapy and activation of immune systems during infection.
Gilles Guichard (Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France)
Additional contact for comment on paper:
Sarah Hymowitz (Genentech, Inc., South San Francisco, California, USA)
Abstract available online: Guichard Paper.
(C) Nature Chemical Biology press release.
Message posted by: Trevor M. D'Souza