Simple synthetic toll-like receptor 2 ligands

Abdel-Aal, Abu-Baker M., Al-Isae, Kalifa, Zaman, Mehfuz and Toth, Istvan (2011) Simple synthetic toll-like receptor 2 ligands. Bioorganic and Medicinal Chemistry Letters, 21 19: 5863-5865. doi:10.1016/j.bmcl.2011.07.102

Author Abdel-Aal, Abu-Baker M.
Al-Isae, Kalifa
Zaman, Mehfuz
Toth, Istvan
Title Simple synthetic toll-like receptor 2 ligands
Journal name Bioorganic and Medicinal Chemistry Letters   Check publisher's open access policy
ISSN 0960-894X
Publication date 2011-10-01
Year available 2011
Sub-type Article (original research)
DOI 10.1016/j.bmcl.2011.07.102
Open Access Status Not Open Access
Volume 21
Issue 19
Start page 5863
End page 5865
Total pages 3
Place of publication East Park, Kidlington, Oxford, U.K.
Publisher Pergamon
Language eng
Abstract Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogues with a well-defined spacer length (∼25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers.
Formatted abstract
Stimulation of toll-like receptor 2 (TLR2) by bacterial lipoproteins induces fast non-specific immune responses against pathogens followed by slow but specific adaptive immune responses. Development of synthetic TLR2 agonists/antagonists would be useful in the prevention of different infectious and immunologic disorders. The current study reports synthesis and TLR2 activity of two simple TLR2 ligands, which feature minimal structural requirement for TLR2 activity (two long lipid chains) and stimulate agonistic activity at nanomolar concentration.
Keyword Toll-like receptor 2
Lipoamino acid
Lipidic amino-acids
Ceramide analogs
Innate immunity
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID GGP12207
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
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Citation counts: TR Web of Science Citation Count  Cited 17 times in Thomson Reuters Web of Science Article | Citations
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