Differential selectivity of hyaluronidase inhibitors toward acidic and basic hyaluronidases

Tadahiro Isoyama, Dwayne Thwaites, Marie G. Selzer, Robert I. Carey, Rolando Barbucci, Vinata B. Lokeshwar

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Hyaluronidase (HAase), a class of enzymes which degrade hyaluronic acid (HA), are involved in the spread of infections/toxins, ovum fertilization, and cancer progression. Thus, HAase inhibitors may have use in disease treatments. We evaluated 21 HAase inhibitors against HYAL-1, testicular, honeybee, and Streptomyces HAases. Among these inhibitors, polymers of poly (styrene-4-sulfonate) (PSS) (i.e., molecular weight 1400-990,000 or PSS 1400-PSS 990,000) and O-sulfated HA (sHA) derivatives (sHA2.0, 2.5, and 2.75) were the most effective. HYAL-1 and bee HAases were the most sensitive, followed by testicular HAase; Streptomyces HAase was resistant to all inhibitors, except PSS 990,000 and VERSA-TL 502 (i.e., PSS 106 dalton). The length of the PSS polymer determined their potency (e.g., IC50 for HYAL-1, PSS 990,000: 0.0096 μM; PSS 210 no inhibition; IC50 for testicular HAase, PSS 990,000: 0.042 μM; PSS 210 no inhibition). The presence, but not the number, of sulfate groups on the sHA molecule determined its potency (e.g., IC50 for HYAL-1: sHA2.0, 0.019 μM; sHA2.75, 0.0083 μM). Other known HAase inhibitors, such as gossypol, sodium-aurothiomalate, 1-tetradecane sulfonic acid, and glycerrhizic acid, were not effective. Both PSS and sHA inhibited HAases by a mixed inhibition mechanism (i.e., competitive + uncompetitive) and were 5- to 17-fold better as uncompetitive inhibitors than as competitive inhibitors. These results demonstrate that HAase inhibitors show selectivity toward the different types of HAases, which could be exploited to inhibit specific HAases involved in a variety of pathophysiologic conditions.

Original languageEnglish (US)
Pages (from-to)11-21
Number of pages11
JournalGlycobiology
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2006

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Keywords

  • HYAL1
  • Hyaluronic acid
  • Hyaluronidase
  • Hyaluronidase inhibitors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Isoyama, T., Thwaites, D., Selzer, M. G., Carey, R. I., Barbucci, R., & Lokeshwar, V. B. (2006). Differential selectivity of hyaluronidase inhibitors toward acidic and basic hyaluronidases. Glycobiology, 16(1), 11-21. https://doi.org/10.1093/glycob/cwj036