Background/Purpose: Osteoarthritis (OA) is a disease which results in the degeneration of articular cartilage. The progression of OA involves inflammation in the early stage of the disease which induces the activation of cartilage-degrading enzymes, such as metalloproteases (MMPs) and aggrecanases (ADAMTSs), through different signaling pathways. Based on the literature, MMP3 can be considered a promising target in OA therapy: in detail, several clinical studies reported an increase of MMP3 level in synovial fluid (SF) in early and advanced OA patients. In our previous work a hyaluronic acid (HA) partial hexadecylamide (HYADD^®4), contained in the viscosupplement Hymovis^®, was selected as the strongest MMP and hyaluronidase inhibitor among a series of glycosaminoglycans. The objective of these further studies was to confirm the in vitro efficacy and selectivity of HYADD^®4 as MMP inhibitor and to elucidate the mechanism of inhibition through in silico studies

Methods: HYADD^®4 was screened in vitro against 10 different human MMPs and other targets. In order to shed light on the mechanism of inhibition, the structural interactions between a HYADD^®4 oligomer and the crystal structure of MMP3 were evaluated in silico by means of molecular modeling studies. Molecular docking and molecular dynamics simulations were performed to propose a hypothetical binding mode of the HYADD^®4 oligomer on MMP3 and to evaluate the stability of the complex

Results: Among the tested glycosaminoglycans HYADD^®4 showed the highest inhibition potency against MMP13, MMP8 and MMP3, and no activity against ADAMTS4 and elastase in vitro. The molecular modeling results suggest that HYADD^®4 may behave as a competitive MMP inhibitor, because of its ability to interact with the collagen-binding groove and to participate in the coordination of the catalytic zinc ion of this class of enzymes. Moreover, the hexadecyl side chain in HYADD^®4 is suitable to fit effectively the enzyme S1’ additional pocket, increasing its affinity for MMP3

Conclusion: The HA derivative HYADD^®4 showed an inhibitory effect on MMP activity in vitro; in this study, a specific mechanism for the structural inhibition of MMP3 has been proposed on the basis of molecular simulation studies. A subsequent pivotal clinical trial has been performed to confirm the efficacy of HYADD^®4 in inhibiting MMP3 activity in the synovial fluid of OA patients in comparison with another viscosupplement based on a different HA chemistry. These findings suggest that the intra-articular administration of HYADD^®4 (Hymovis^®) may prevent local cartilage degradation mediated by MMPs

ACR Meeting Abstracts - https://acrabstracts.org/abstract/effective-inhibition-of-metalloproteases-by-a-viscosupplement-based-on-a-hyaluronic-acid-amide-hyadd4/