Hyaluronidase Inhibitors: A Biological and Therapeutic Perspective

Abstract

The hyaluronidases (HAases) are a group of less extensively studied glycosidases distributed throughout the animal kingdom and are popularly known as 'spreading factors'. In recent years, HAases received much attention due to their ability to abruptly alter the hyaluronic acid (HA) homeostasis. HAases preferentially degrade HA, which is a megadalton acidic structural polysaccharide found exclusively in the extracellular matrix (ECM) of animals. The HA-HAase system has been suggested to participate in many pathophysiological conditions. The HA degradation in ECM, crack down the structural integrity with an eventual increased tissue permeability that is attributed for the spreading property. The spreading property has been widely accepted in functions including envenomation, acrosomal reaction/ovum fertilization, cancer progression, microbial pathogenesis such as wound infections, pneumonia, and other sepses like, bacteremia and meningitis. HA fragmentation has dual effects; generation of a wide molecular range bioactive oligosaccharides of angiogenic, pro-inflammatory, and immunostimulatory properties; and impairment in the reservoir capacity of ECM that holds metal ions, growth factors, cytokines and various enzymes for signal transduction. Hence, inhibition of HA degradation appears critical and imperative in HAase mediated pathological conditions. HAase inhibitors are thus potent regulators that maintain HA homeostasis and they might serve as anti-inflammatory, anti-aging, anti-microbial, anticancer and anti-venom/toxin and contraceptive agents. In addition, HAase inhibitors may serve as tools to understand several unexplained and complex functions of HAases in HA metabolism. Therefore, this review is expected to provide an integrated update as of 2008 on the HAase inhibitors and their possible role as therapeutics in the management of a wide range of pathological conditions.

Hyaluronidase-inhibitory activities of glycosaminoglycans from Liparis tessellatus eggs

“…Thus, the high activity of F3 could be attributed to its uronic acids content. In addition, the presence of sulfated glycans in this fraction (Table 1) This observation can affirm the hyaluronidase inhibitory effect of F3 fraction, since, as a hyaluronidase inhibitor, it can deter HA fragmentation which can promote inflammation (Girish et al, 2009). In line with this observation, sulfated hyaluronic acid (sHA) (Benitez et al, 2011;Furusawa et al, 2011) was found out to inhibit the activity of hyaluronidases by a mixed inhibition mechanism, where the tumor-derived hyaluronidase was found out to be inhibited by sHA, a nontoxic hyaluronidase inhibitor.…”

“…At the same time, sHA also delineated the molecular mechanism through which hyaluronic acid-hyaluronidase (HA-HAase) system might mediate tumor growth and progression, since HA-HAase is known to promote tumor growth and metastasis (Simpson & Lokeshwar, 2008). Hence, inhibition of HA degradation appears critical and imperative in HAase mediated pathological conditions (Girish et al, 2009). …”

“…These compounds are potent regulators that maintain hyaluronidase homeostasis and might serve as anti-inflammatory (Girish, Kemparaju, Nagaraju, & Vishwanath, 2009) and anti-allergen agents (Mase et al, 2013), wherein they counteract the implication of hyaluronidase in tumor invasiveness and homeostasis (Madan et al, 1999).…”

Cyclic Spermidine Alkaloids and Flavone Glycosides from Meehania fargesii

“…Rosmarinic acid, lithospermic acid B, diosmetin-7-O-b-D-glucuronide, and apigenin-7-O-b-D-glucuronide were identified as hyaluronidase inhibitors. Two new cyclic spermidine alkaloids, meefarnines A and B (1, 2), four new flavone glycosides, fargenins A-D (3)(4)(5)(6), and the methyl ester (4a) of 4 have also been isolated together with 10 known compounds and we describe the elucidation of their structure.…”

“…3,4) Moreover, they are potent anti-inflammatory, anti-aging, and anti-cancer agents. 5) In the present study, we investigated constituents of fractions which showed strong hyaluronidase inhibitory activity from whole plants of M. fargesi. Rosmarinic acid, lithospermic acid B, diosmetin-7-O-b-D-glucuronide, and apigenin-7-O-b-D-glucuronide were identified as hyaluronidase inhibitors.…”