Natural compounds as human Hyaluronidase Hyal-1 inhibitors

Lengers I, Orlando Z, Melzig MF, Buschauer A, Hensel A, Jose J

Abstract

The polysaccharide hyaluronic acid (HA) plays an important role in cancer progression. Its physiological and pathophysiological functions depend on its chain size. Space-filling, anti-inflammatory andantiangiogenic effects are caused by high molecular weight HA (>20 kDa). HA hydrolization by hyaluronidases leads to low molecular weight HA (<20 kDa), resulting in inflammatory and angiogenic effects [1].The degradation of HA is mainly catalyzed by human hyaluronidase Hyal-1. It has been demonstrated that in prostate or bladder tumour cells the expression level of Hyal-1 was elevated. For this reason Hyal-1 isan interesting target for drug discovery [2, 3]. The surface display of active Hyal-1 on Escherichia coli via Autodisplay, facilitates screening for potential inhibitors in a whole cell system. Based on this technique wedetermined the inhibitory effect of different plant extracts and triterpenoid saponins on human Hyal-1. The IC50 values of the extracts of Malvae sylvestris flos, Equiseti herba and Ononidis radix were determined tobe between 1.4 and 1.7 mg/mL. Furthermore, the IC50 values of four triterpenoid saponins were determined. The obtained IC50 value for glycyrrhizic acid, a known Hyal-1 inhibitor, was 177 μM. The IC50 values forthe newly identified inhibitors gypsophila saponin 2, SA1641, and SA1657 were determined to be 108 μM, 296 μM and 371 μM, respectively [4]. For the synthesis of new small molecule inhibitors targeting humanHyal-1 these extracts and natural compounds could be used as starting points.