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Small Molecules Target Toll-Like Receptors

ACS Meeting News: New small-molecule screens tackle protein-protein interactions important in myriad diseases

by Carmen Drahl
August 27, 2012 | A version of this story appeared in Volume 90, Issue 35

Credit: Courtesy of Hang (Hubert) Yin
In this molecular model, the Yin team’s probe (spacefill) binds at the interface of TLR1 and TLR2 (ribbon).
The protein complex between Toll-like receptor 1 (pink ribbon) and Toll-like receptor 2 (orange ribbon) can be probed with small molecule CU-CPT22 (spacefill). Binding interaction determined by molecular modeling
Credit: Courtesy of Hang (Hubert) Yin
In this molecular model, the Yin team’s probe (spacefill) binds at the interface of TLR1 and TLR2 (ribbon).

Aided by high-throughput screening, chemists have found new ways to target Toll-like receptors (TLRs), membrane-spanning proteins that provoke inflammation and immune responses. The research might speed development of new treatments for infectious diseases or cancer. It’s proven tough to disrupt the complexes TLRs form with proteins or genetic material, explained Hang (Hubert) Yin of the University of Colorado, Boulder. Yin’s team has developed screens to rectify that. One of their assays, conducted in macrophage cells that contain all types of TLRs, monitors production of nitric oxide, an indicator of receptor activity. In Philadelphia, Yin explained how optimizing hits from that assay and others led to inhibitors for complexes involving TLR3 and TLR4. In not-yet-published work, his team has developed the first small-molecule probe for the complex between TLR1 and TLR2, implicated in autoimmune diseases and cancers. The probe, called CU-CPT22, is specific for TLR1/2 and might be useful for evaluating more druglike inhibitors, Yin said. Yin “is clearly targeting an important series of challenges in medicine,” said Lisa McElwee-White of the University of Florida, who moderated the session at which Yin spoke. “His work is an excellent illustration of how small molecules can tackle biological problems.”


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