title: 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 s.c. and oral routes. 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.
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA.
authors.forename: Rafaz
authors.initials: R
authors.lastname: Hoque
authors.forename: Ahmad
authors.initials: A
authors.lastname: Farooq
authors.forename: Ahsan
authors.initials: A
authors.lastname: Malik
authors.forename: Bobby N
authors.initials: BN
authors.lastname: Trawick
authors.forename: David W
authors.initials: DW
authors.lastname: Berberich
authors.forename: Joseph P
authors.initials: JP
authors.lastname: McClurg
authors.forename: Karen P
authors.initials: KP
authors.lastname: Galen
authors.forename: Wajahat
authors.initials: W
authors.lastname: Mehal
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use; D000818:Animals; D017321:Clinical Trials, Phase I as Topic / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000627:therapeutic use*; D008024:Ligands; D017114:Liver Failure, Acute / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009019:Morphinans / Q000737:chemistry* / Q000627:therapeutic use*; D010195:Pancreatitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013237:Stereoisomerism; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D008024:Ligands; D009019:Morphinans; D017450:Receptors, Opioid, mu; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D000082:Acetaminophen