Computer-designed protein targets immune receptor linked to inflammation at new 'undruggable' site
To sense their environment and respond accordingly, cells enlist membrane proteins as communication hubs, receiving molecular messages from outside and triggering responses inside. One of these proteins is Toll-like receptor 4 (TLR4), an immune receptor that plays an essential role in protecting against infections. But overactivity of TLR4 has been linked to inflammatory disorders like sepsis,…
A new study from Scripps Research has engineered a synthetic protein that targets an undruggable site on the Toll-like receptor 4 (TLR4) immune receptor, blocking inflammatory responses. TLR4, an essential immune receptor, has been linked to inflammatory disorders when overactive. No FDA-approved drugs specifically block TLR4, making it a challenging target for therapies.
The research team at Scripps Research discovered that the membrane-spanning region of TLR4, previously thought to passively attach it to the cell membrane, plays an active role in determining inflammatory responses. By designing a synthetic protein that binds more effectively within this region, the team aimed to reduce TLR4-initiated inflammation.
They used computer programs to generate 3D protein structures, optimizing them for apolar packing within the greasy cell membrane. The resulting synthetic protein, Design-6, showed significant potential in reducing NF-κB inflammatory signaling when tested in human cell cultures. This breakthrough opens up new possibilities for developing anti-inflammatory treatments targeting previously inaccessible regions of TLR4.
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