An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies.
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.
Dipartimento di Scienze Chimiche, Università di Napoli "Federico II", via Cintia 21, Complesso Universitario di Monte Sant'Angelo, I-80126 Napoli, Italy. Electronic address: domymusu@alice.it.
Domenica
D
Musumeci
Istituto di Biostrutture e Bioimmagini - CNR, via Mezzocannone 16, I-80134 Napoli, Italy.
Giovanni N
GN
Roviello
Dipartimento di Scienze Chimiche, Università di Napoli "Federico II", via Cintia 21, Complesso Universitario di Monte Sant'Angelo, I-80126 Napoli, Italy.
Daniela
D
Montesarchio
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000503:physiopathology; D015195:Drug Design; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
DNA-based inhibitors; EP; GL; HMGB; HMGB1; HMGB1-receptors; High-Mobility Group Box; I/R; IL; LPS; ODN; PNA; Peptide/protein inhibitors; RAGE; Small-molecule inhibitors; TLR; TNF; ethyl pyruvate; glycyrrhizin; interleukin; ischemia–reperfusion; lipopolysaccharide; oligodeoxyribonucleotide; peptide nucleic acid; receptor for advanced glycation end products; toll-like receptor; tumor necrosis factor