A Novel Small-Molecule Enantiomeric Analogue of Traditional (−)-Morphinans Has Specific TLR9 Antagonist Properties and Reduces Sterile Inflammation-Induced Organ Damage

Abstract

TLR9 is a key determinant of the innate immune responses in both infectious and sterile injury. Specific antagonism of TLR9 is of great clinical interest to reduce tissue damage in a wide range of pathologies, and has been approached by modification of nucleic acids, the recognized ligand for TLR9. Such oligonucleotide-derived pharmacotherapeutics have limitations in specificity for nucleic acid receptors, significant potential for immunologic recognition with generation of innate and adaptive immune responses, and limited bioavailability. We have identified enantiomeric analogues of traditional (−)-morphinans as having TLR9 antagonist properties on reporter cell lines. One of these analogues (COV08-0064) is demonstrated to be a novel small molecule antagonist of TLR9 with greater specificity for TLR9 than oligo based antagonists. COV08-0064 has wide bioavailability, including the subcutaneous and per oral route. It specifically inhibits the action of TLR9 antagonists on reporter cells lines and the production of cytokines by TLR9 agonists from primary cells. It also has efficacy in limiting TLR9 mediated sterile inflammation in in vivo models of acute liver injury and acute pancreatitis. The identification of a morphinan based novel small molecule structure with TLR9 antagonism is a significant step in expanding therapeutic strategies in the field of sterile inflammatory injury.

Toll-Like Receptor 9-Mediated Inflammation Triggers Alveolar Bone Loss in Experimental Murine Periodontitis

“…To our knowledge, this is the first in vivo demonstration that a nucleic acid sensor, TLR9, can mediate destructive periodontal inflammation and can therefore be considered a potential therapeutic target for periodontal disease. Small-molecule inhibitors of TLR9 signaling are already commercially available and are being evaluated for the treatment of various inflammatory disorders (53)(54)(55). Our findings provide for the first time a strong mechanistic rationale for investigating the efficacy of TLR9 small-molecule inhibitors in controlling periodontitis in a preclinical setting and, ultimately, in future clinical trials.…”

Promising Therapy Candidates for Liver Fibrosis

“…Pharmacological inhibition of TLR4 by Eritoran tetrasodium ameliorates liver injury through blocking HMGB1-mediated inflammatory signaling in ischemia and reperfusion mice (McDonald et al, 2015 ) In addition, both bacterial DNA and mitochondrial DNA and nuclear DNA released by damaged hepatocyte can activate TLR9 and induce a number of cellular immune responses (Kubes and Mehal, 2012 ). A specific antagonist of TLR9, COV08-0064, could limit the sterile inflammation in rat and mouse models of acute liver injury and acute pancratitis (Hoque et al, 2013 ). So, the antagonists of TLRs provide us new options of combination drug therapy for controlling liver inflammation.…”

Effects of Toll‑like receptor 9 and CpG oligodeoxynucleotides 1826 on sodium taurocholate‑induced acute pancreatitis rats

“…Additionally, TLR9 protein expression was upregulated subsequent to AP. TLR9 is a key determinant of the innate immune response in infectious and sterile injury ( 13 ). Previously, Hoque et al ( 2 ) demonstrated that host genomic DNA is markedly elevated in the blood very early in the course of experimental AP, which is consistent with a role for TLR9 in sensing initial pancreatic injury.…”