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Glycobiology Advance Access published online on September 15, 2005
Glycobiology, doi:10.1093/glycob/cwj036
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Received February 25, 2005
Revised September 2, 2005
Accepted September 3, 2005

Article

Differential Selectivity of Hyaluronidase Inhibitors towards Acidic and Basic Hyaluronidases

Tadahiro Isoyama 1 +, Dwayne Thwaites 1 +, Marie G. Selzer 1, Robert I. Carey 1, Rolando Barbucci 2, and Vinata B. Lokeshwar 3*

1 Department of Urology, University of Miami Miller School of Medicine, Miami, Florida
2 Department of Chemical and Biosystem Sciences and Technologies and C.R.I.S.M.A., University of Siena, Siena, Italy
3 Departments of Urology, Cell Biology and Anatomy and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida

* To whom correspondence should be addressed.
Vinata B. Lokeshwar, E-mail: vlokeshw{at}med.miami.edu


  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) (i.e., mol wt 1400 to 990,000 or PSS 1400 to PSS 990,000) and O-sulfated HA 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 5-17-fold better as uncompetitive inhibitors than as competitive inhibitors. These results demonstrate that HAase inhibitors show selectivity towards the different types of HAases, which could be exploited to inhibit specific HAases involved in a variety of pathophysiologic conditions.

Keywords: Hyaluronic acid/Hyaluronidase/Hyaluronidase inhibitors/HYAL1/testicular hyaluronidase/bee hyaluronidase/Streptomyces hyaluronidase.

+: Both authors contributed equally to this work


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