Folic acid derived-P5779 mimetics regulate DAMP-mediated inflammation through disruption of HMGB1:TLR4:MD-2 axes.
High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) protein that mediates inflammatory responses after infection or injury. Previously, we reported a peptide inhibitor of HMGB1 (P5779) that acts by directly interrupting HMGB1/MD-2 binding. Here, fingerprint similarity s...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5814057?pdf=render |
| Summary: | High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) protein that mediates inflammatory responses after infection or injury. Previously, we reported a peptide inhibitor of HMGB1 (P5779) that acts by directly interrupting HMGB1/MD-2 binding. Here, fingerprint similarity search and docking studies suggest folic acid derived-drugs function as P5779 mimetopes. Molecular dynamic (MD) simulation studies demonstrate that folic acid mimics the binding of P5779 at the TLR4 and MD-2 intersection. In surface plasmon resonance (SPR) studies, these drugs showed direct binding to TLR4/MD-2 but not HMGB1. Furthermore, these P5779 mimetopes inhibit HMGB1 and MD-2 binding and suppress HMGB1-induced TNF release in human macrophages in the nanomolar range. We assert from our findings that their demonstrated anti-inflammatory effects may be working through TLR4-dependent signaling. |
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| ISSN: | 1932-6203 |