Isoyama Tadahiro, Thwaites Dwayne, Selzer Marie G, Carey Robert I, Barbucci Rolando, Lokeshwar Vinata B
Department of Urology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Glycobiology. 2006 Jan;16(1):11-21. doi: 10.1093/glycob/cwj036. Epub 2005 Sep 15.
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 10(6) dalton). The length of the PSS polymer determined their potency (e.g., IC50 for HYAL-1, PSS 990,000: 0.0096 microM; PSS 210 no inhibition; IC50 for testicular HAase, PSS 990,000: 0.042 microM; 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 microM; sHA2.75, 0.0083 microM). 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.
透明质酸酶（HAase）是一类可降解透明质酸（HA）的酶，参与感染/毒素扩散、卵子受精及癌症进展过程。因此，HAase抑制剂可能具有疾病治疗用途。我们评估了21种HAase抑制剂对HYAL-1、睾丸、蜜蜂及链霉菌来源的HAase的作用。在这些抑制剂中，聚（苯乙烯-4-磺酸盐）（PSS）聚合物（即分子量1400 - 990,000或PSS 1400 - PSS 990,000）和O-硫酸化HA（sHA）衍生物（sHA2.0、2.5和2.75）最为有效。HYAL-1和蜜蜂来源的HAase最为敏感，其次是睾丸来源的HAase；链霉菌来源的HAase对所有抑制剂均有抗性，但对PSS 990,000和VERSA-TL 502（即PSS 10⁶道尔顿）除外。PSS聚合物的长度决定了它们的效力（例如，对HYAL-1的IC50，PSS 990,000：0.0096微摩尔；PSS 210无抑制作用；对睾丸HAase的IC50，PSS 990,000：0.042微摩尔；PSS 210无抑制作用）。sHA分子上硫酸基团的存在而非数量决定了其效力（例如，对HYAL-1的IC50：sHA2.0，0.019微摩尔；sHA2.75，0.0083微摩尔）。其他已知的HAase抑制剂，如棉酚、金硫代苹果酸钠、1-十四烷磺酸和甘草次酸，均无效。PSS和sHA均通过混合抑制机制（即竞争性+非竞争性）抑制HAase，且作为非竞争性抑制剂的效果比作为竞争性抑制剂好5至17倍。这些结果表明，HAase抑制剂对不同类型的HAase具有选择性，这可用于抑制参与多种病理生理状况的特定HAase。
