title: Hyaluronic acid alkyl derivative: A novel inhibitor of metalloproteases and hyaluronidases.
abstract: Extracellular matrix (ECM) degradation, one of the main features of osteoarthritis, is driven by at least two major classes of enzymes: matrix metalloproteases (MMPs) and hyaluronidases. Among certain glycosaminoglycans, including natural and chemically cross-linked HAs, which are currently used as viscosupplements, the hyaluronic acid (HA) alkyl-amides (Hyadd) were here selected as the strongest MMP and hyaluronidase inhibitors. We used C. histolyticum collagenase (ChC) and bovine testicular hyaluronidase (BTH) as representative models of human MMPs and hyaluronidases, respectively. The role of the alkyl moiety was investigated using HA derivatives with varying alkyl lengths and degrees of derivatization. The selected compound was then screened against 10 different human MMPs in vitro, and the results were validated ex vivo in human synovial fluid. Hyadd-C16, identified as a lead compound, showed the highest inhibition potency against MMP13 and MMP8. The in vitro results were confirmed by the inhibition of human MMP13 (Ki=106.1 μM) and hyaluronidase-2 in the synovial fluid of patients with osteoarthritis. This study demonstrates the unique properties of Hyadd-C16, including its remarkable enzymatic inhibitory activity, which is conferred by the hydrophobic chain, and its high biocompatibility and water solubility of the HA backbone.
authors.affiliation: Fidia Farmaceutici s.p.a., via Ponte della Fabbrica 3/A, 35031 Abano Terme, PD, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pavan
authors.affiliation: Fidia Farmaceutici s.p.a., via Ponte della Fabbrica 3/A, 35031 Abano Terme, PD, Italy.
authors.forename: Devis
authors.initials: D
authors.lastname: Galesso
authors.affiliation: Fidia Farmaceutici s.p.a., via Ponte della Fabbrica 3/A, 35031 Abano Terme, PD, Italy.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Secchieri
authors.affiliation: Fidia Farmaceutici s.p.a., via Ponte della Fabbrica 3/A, 35031 Abano Terme, PD, Italy. Electronic address: cguarise@fidiapharma.it.
authors.forename: Cristian
authors.initials: C
authors.lastname: Guarise
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006821:Hyaluronoglucosaminidase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D045726:Metalloproteases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases
keywords: Hyaluronan; Matrix metalloproteinase (MMP); Osteoarthritis