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Identification of a pyrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual
Maria Grabowski1, Manuela S Murgueitio2, Marcel Bermudez2
1Freie Universität Berlin, Institute of Pharmacy (Pharmacology and Toxicology), Germany.
Abstract:
Toll-like receptor 2 (TLR2) induces early inflammatory responses to pathogen and damage-associated molecular patterns trough heterodimerization with either TLR1 or TLR6. Since overstimulation of TLR2 signaling is linked to several inflammatory and metabolic diseases, TLR2 antagonists may provide therapeutic benefits for the control of inflammatory conditions. We present virtual screening for the identification of novel TLR2 modulators, which combines analyses of known ligand sets with structure-based approaches. The 13 identified compounds were pharmacologically characterized in HEK293-hTLR2 cells, THP-1 macrophages and peripheral blood mononuclear cells for their ability to inhibit TLR2-mediated responses. Four out of 13 selected compounds show concentration-dependent activity, representing a hit rate of 31%. The most active compound is the pyrogallol derivative MMG-11 that inhibits both TLR2/1 and TLR2/6 signaling and shows a higher potency than the previously discovered CU-CPT22. Concentration ratio analysis identified both compounds as competitive antagonists of Pam3CSK4- and Pam2CSK4-induced responses. Schild plot analysis yielded apparent pA2 values of 5.73 and 6.15 (TLR2/1), and 5.80 and 6.65 (TLR2/6) for CU-CPT22 and MMG-11, respectively. MMG-11 neither shows cellular toxicity nor interference with signaling induced by other TLR agonists, IL-1β or TNF. Taken together, we demonstrate that MMG-11 is a potent and selective TLR2 antagonist with low cytotoxicity rendering it a promising pharmacological tool for the investigation of TLR signaling and a suitable lead structure for further chemical optimization.
Insights
Toll-like receptor 2 (TLR2) antagonists, like MMG-11, can inhibit inflammatory responses. This study identified MMG-11 as a potent and selective TLR2 antagonist with low toxicity, useful for research and drug development.
Area of Science:
- Immunology
- Pharmacology
- Medicinal Chemistry
Background:
- Toll-like receptor 2 (TLR2) plays a key role in initiating inflammatory responses.
- Overactivation of TLR2 signaling is implicated in various inflammatory and metabolic diseases.
- Targeting TLR2 with antagonists offers a potential therapeutic strategy for managing inflammatory conditions.
Purpose of the Study:
- To identify novel modulators of Toll-like receptor 2 (TLR2) using virtual screening.
- To characterize the inhibitory potential of identified compounds against TLR2-mediated signaling.
- To evaluate the lead compound MMG-11 as a potent and selective TLR2 antagonist.
Main Methods:
- Virtual screening combining ligand-based and structure-based approaches to identify potential TLR2 modulators.
- Pharmacological characterization of 13 selected compounds in HEK293-hTLR2 cells, THP-1 macrophages, and peripheral blood mononuclear cells.
- Inhibition assays for TLR2-mediated responses, including concentration-response and Schild plot analyses.
Main Results:
- Four out of 13 screened compounds demonstrated concentration-dependent inhibition of TLR2 signaling, achieving a 31% hit rate.
- The pyrogallol derivative MMG-11 emerged as the most potent compound, inhibiting both TLR2/1 and TLR2/6 heterodimer signaling.
- MMG-11 exhibited competitive antagonism and superior potency compared to CU-CPT22, with no observed cellular toxicity or off-target effects.
Conclusions:
- MMG-11 is a potent and selective Toll-like receptor 2 (TLR2) antagonist with low cytotoxicity.
- MMG-11 serves as a valuable pharmacological tool for studying TLR signaling pathways.
- The compound's structure provides a promising lead for the development of novel therapeutics targeting TLR2-mediated inflammatory diseases.
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