Selective inhibition of cathepsin S elastolytic activity by exopolysaccharides from deep-sea hydrothermal bacteria

Human cathepsin S (CatS) constitutes a key orchestrator of extracellular matrix (ECM) remodeling. Recent evidence suggest that CatS inhibition is a valuable therapeutic option for inflammatory diseases that are characterized by an excessive degradation of insoluble elastin, a process in which CatS contributes significantly when it is overexpressed. Here, we report novel findings that highlight the inhibition of CatS by two low-molecular weight highly sulphated exopolysaccharides (EPS), named diabolican (Dia_9-Hsulf) and infernan (Inf_19-Hsulf), derived from two marine bacterial strains Vibrio diabolicus and Alteromonas infernus, respectively. Dia_9-Hsulf and to a lesser extent Inf_19-Hsulf were selective and potent uncompetitive inhibitors of CatS (nanomolar range), which represents an unprecedented mechanism of CatS inhibition. In addition, both EPS selectively inhibited the elastolytic activity of CatS, without affecting the degradation of its other biological substrates (e.g. collagen, thyroglobulin). Combined experimental and in silico approaches provided new insights on how highly sulfated diabolican prevented the CatS elastolytic activity by hindering its elastin-binding exosite. These results evidenced EPS as promising molecules to preserve the elastin integrity during inflammatory events implying CatS.