Toll-like receptors (TLRs), a class of pattern recognition receptors (PRRs), are important regulators of inflammation and host resistance. Binding of ligands (PAMPs/DAMPs) to the ectodomain of hetero- or homodimeric TLR pairs activates signal transduction cascades resulting in the production of pro-inflammatory cytokines, type-I interferons (IFN) and chemokines. TLRs 7/8/9 are a subset of the TLR family that are endosomally located and respond to either single stranded RNA (TLR 7/8) or single stranded DNA (TLR9). This ligand binding event induces a dimerization of the TLR thus creating two identical binding sites. Herein, we describe our efforts to connect a known TLR 7/8 antagonist with various linkers in an effort to bind both sites of the homodimeric TLR pair. Antagonist activity for these dimerized compounds against TLRs 7/8/9 as well as selectivity versus other TLR family members will be presented. As shown in Figure 1, an X-ray co-crystal structure reveals both symmetrical binding sites of TLR8 occupied by a dimeric antagonist, with each fragment retaining the key ligand-protein interactions of the monomers. A comparison of monomeric to dimeric ligands in terms of potency, selectivity, and other properties will be detailed.

Dimeric antagonists of endosomal toll-like receptors 7, 8 and 9 (TLR7/8/9)

ACS Spring 2022

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