TREM-1 and TREM-2 as therapeutic targets: clinical challenges and perspectives

Abstract

TREM-1 and TREM-2 as Therapeutic Targets: Clinical Challenges and Perspectives.

Keywords: TREM-1; TREM-2; antagonists & inhibitors; clinical trial failure; drug discovery & development; inflammation; ligand-independent inhibition; multiligand receptors.

Figure 1

TREM-1: receptor assembly, signaling and mechanisms of ligand-dependent and ligand-independent inhibition (A) TREM-1/DAP-12 receptor complex assembly and signaling are depicted. TREM-1 and DAP-12 are bound together by electrostatic interactions between their basic and acidic amino acids in the cell membrane. Binding to the known and unknown natural human ligands of TREM-1 results in dimerization/multimerization of the TREM-1/DAP-12 complex followed by homooligomerization of cytoplasmic DAP-12 domains that triggers the receptor. (B) Ligand-dependent inhibitors attempt to block interaction of TREM-1 with its multiple ligands by binding with either the ligands (decoy peptides) or TREM-1 (anti-TREM-1 blocking antibodies, peptides and small molecules). (C) Ligand-independent peptide inhibitor GF9 (SCHOOL mechanism-based peptide) disrupts the interactions between TREM-1 and DAP-12 in the cell membrane that upon binding to the ligands, results in dimerization/multimerization of only TREM-1 but not DAP-12, therefore completely blocking the transmembrane signaling. GF9 can reach its site of action in the cell membrane from not only outside but also inside the cell enabling targeted intracellular delivery of GF9 peptide sequence-based TREM-1 inhibitor to certain types of TREM-1-expressing cells. eCIRP, extracellular cold-inducible RNA-binding protein; HMGB1, high mobility group box 1; Hsp70, heat shock protein 70 kDa; PGLYRP1, peptidoglycan recognition protein 1; SCHOOL, signaling chain homooligomerization.