title: Progress towards the identification of new aggrecanase inhibitors.
abstract: Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by "aggrecanases". Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Zn-chelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.
authors: Department of Chemistry, University of Modena and Reggio Emilia, Via G. Campi 183, Modena, Italy.
authors: Francesca
authors: F
authors: De Rienzo
authors: Puneet
authors: P
authors: Saxena
authors: Federico
authors: F
authors: Filomia
authors: Gianfranco
authors: G
authors: Caselli
authors: Fabrizio
authors: F
authors: Colace
authors: Luigi
authors: L
authors: Stasi
authors: Antonio
authors: A
authors: Giordani
authors: Maria Cristina
authors: MC
authors: Menziani
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D001168:Arthritis / Q000188:drug therapy; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D053674:Aggrecans; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011480:Protease Inhibitors; D010450:Endopeptidases; C083641:aggrecanase