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Abstract Number: 2004

Effective Inhibition of Metalloproteases By a Viscosupplement Based on a Hyaluronic Acid Amide (HYADD®4)

Cynthia Secchieri1, Devis Galesso1, Cristian Guarise1, Mauro Pavan1, Stefano Moro2 and Veronica Salmaso2, 1Fidia Farmaceutici, Abano Terme, Italy, 2Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: cartilage, hyaluronate, osteoarthritis and viscosupplementation

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Session Information

Date: Tuesday, October 23, 2018

Title: Osteoarthritis and Joint Biology – Basic Science Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

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


Disclosure: C. Secchieri, Fidia Farmaceutici, 3; D. Galesso, Fidia Farmaceutici, 3; C. Guarise, Fidia Farmaceutici, 3; M. Pavan, Fidia Farmaceutici, 3; S. Moro, Fidia Farmaceutici, 2; V. Salmaso, Fidia Farmaceutici, 2.

To cite this abstract in AMA style:

Secchieri C, Galesso D, Guarise C, Pavan M, Moro S, Salmaso V. Effective Inhibition of Metalloproteases By a Viscosupplement Based on a Hyaluronic Acid Amide (HYADD®4) [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/effective-inhibition-of-metalloproteases-by-a-viscosupplement-based-on-a-hyaluronic-acid-amide-hyadd4/. Accessed .
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