An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies

• Published in: Pharmacology & therapeutics (Oxford) Vol. 141; no. 3; pp. 347 - 357
• Main Authors: MUSUMECI, Domenica, ROVIELLO, Giovanni N, MONTESARCHIO, Daniela
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01-03-2014
• Subjects: Animals; Autoimmune Diseases - drug therapy; Autoimmune Diseases - physiopathology; Biological and medical sciences; Drug Design; Drug intoxications. Doping; HMGB1 Protein - antagonists & inhibitors; HMGB1 Protein - metabolism; Humans; Inflammation - drug therapy; Inflammation - physiopathology; Medical sciences; Molecular Targeted Therapy; Pharmacology. Drug treatments; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; Signal Transduction - drug effects; Protein inhibitor; Peptides; Antibody; Pathogenesis; HMGB1 Protein; Small-molecule inhibitors; Review; HMGB1; HMGBI-receptors; Anatomic pathology; Advanced glycation end products; DNA-based inhibitors; Treatment; Peptide/protein inhibitors; Small molecule; Mechanism of action; Biological receptor; HMGB; PNA; I/R; TNF; LPS; ODN; TLR; interleukin; glycyrrhizin; peptide nucleic acid; IL; GL; HMGB1-receptors; oligodeoxyribonucleotide; EP; RAGE; ethyl pyruvate; High-Mobility Group Box; tumor necrosis factor; receptor for advanced glycation end products; ischemia–reperfusion; toll-like receptor; lipopolysaccharide
• ISSN: 0163-7258; 1879-016X
• DOI: 10.1016/j.pharmthera.2013.11.001

HMGB1 (High-Mobility Group Box-1) is a nuclear protein that acts as an architectural chromatin-binding factor involved in the maintenance of nucleosome structure and regulation of gene transcription. It can be released into the extracellular milieu from immune and non-immune cells in response to various stimuli. Extracellular HMGB1 contributes to the pathogenesis of numerous chronic inflammatory and autoimmune diseases, including sepsis, rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus (SLE), as well as cancer pathogenesis. Interaction of released HMGB1 with the cell-surface receptor for advanced glycation end products (RAGE) is one of the main signaling pathways triggering these diseases. It has been also demonstrated that the inhibition of the HMGB1-RAGE interaction represents a promising approach for the modulation of the inflammatory and tumor-facilitating activity of HMGB1. In this review we describe various approaches recently proposed in the literature to inhibit HMGB1 and the related inflammatory processes, especially focusing on the block of RAGE-HMGB1 signaling. Several strategies are based on molecules which mainly interact with RAGE as competitive antagonists of HMGB1. As an alternative, encouraging results have been obtained with HMGB1-targeting, leading to the identification of compounds that directly bind to HMGB1, ranging from small natural or synthetic molecules, such as glycyrrhizin and gabexate mesilate, to HMGB1-specific antibodies, peptides, proteins as well as bent DNA-based duplexes. Future perspectives are discussed in the light of the overall body of knowledge acquired by a large number of research groups operating in different but related fields.