Identification of novel agonists of the integrin CD11b/CD18

Abstract

We report the identification of novel small molecule agonists of integrin CD11b/CD18, which increased, in a dose-dependent manner, the adhesion of the integrin CD11b/CD18 expressing cells to two physiologically relevant ligands: Fibrinogen and iC3b. Compound 6 showed an ex vivo EC50 of 10.5 μM and in vitro selectivity for binding to the recombinant αA-domain of CD11b/CD18. In silico docking experiments suggest that the compounds recognized a hydrophobic cleft in the ligand-binding αA-domain, implying an allosteric mechanism of modulation of integrin affinity by this novel compound.

Complement Receptor 3 Influences Toll-like Receptor 7/8-Dependent Inflammation

“…In vitro, LA1 promotes CR3-dependent leukocyte adhesion to fibrinogencoated surfaces while also deterring cell de-adhesion with the net effect being a decrease in chemotaxis and trans-endothelial migration (15,16). In vivo, LA1 decreases leukocyte recruitment in rat peritonitis and preserves kidney function in a mouse model of experimental anti-glomerular basement nephritis.…”

“…Reagents-LA1 was selected based on its utility as a compound, which emerged from a screen of CD11b agonists (15). Human Y3 RNA was prepared from hY3 plasmids, kindly provided by Dr. Sandra Wolin (Yale University School of Medicine), as described (4,17).…”

“…Accordingly, this study was initiated to explore the hypothesis that activation of CR3 specifically inhibits TLR7/8 signaling because this should be particularly applicable to diseases in which the dominant autoantibody is reactive with a ribonucleoprotein. The approach exploited leukadhedrin 1 (LA1), a novel small molecule compound that engages CD11b via a highly specific interaction, allosterically activating CR3, and stimulating binding to its known ligands, including iC3b (15,16). Both TLR7/8 agonists and the SSA/Ro-associated RNA, hY3, were used to stimulate TLR7/8 in macrophages generated from the THP-1 cell line and human donors.…”

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

“…Conversely, they have also been shown to negatively regulate signaling by TLRs, TNF receptors, and cytokine receptors (14,17,23,24,(32)(33)(34), which could suppress downstream IFN-I pathways. To test whether pharmacologic activation of CD11b could suppress TLR-dependent responses, and thus be a therapeutic strategy in SLE, we used our recently discovered small-molecule CD11b agonist LA1 as a tool (35,36). LA1 binds to the CD11bA/I domain (CD11bA) in an allosteric pocket (Supplemental Figure 1), enhancing ligand binding.…”

Efficacy of Leukadherin-1 in the Prevention of Hyperoxia-Induced Lung Injury in Neonatal Rats

“…Leukadherin-1 (LA1) is a newly developed small molecule agonist of CD11b/CD18 that contains a core furanyl thiazolidinone chemical structure motif (20,21). LA1 enhances CD11b/CD18-dependent cell adhesion to its ligands, such as ICAM-1, thus reduces leukocyte transendothelial migration and recruitment (20,21).…”