Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease.
Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease.
复制标题
唾液酸酶和唾液酸基转移酶抑制剂：针对致病性和疾病。
DOI：
10.3389/fmolb.2021.705133
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发表时间：
2021
影响因子：
5
通讯作者：
Gloster TM
中科院分区：
文献类型：
--
作者：
Bowles WHD;Gloster TM
唾液酸酶 (SA) 和唾液酸转移酶 (ST) 是负责去除和添加唾液酸到其他聚糖的酶，在病毒、细菌、寄生虫和人类中发挥着重要作用。唾液酸通常是人类细胞表面突出的聚糖上的末端糖，是识别和细胞功能的重要组成部分。病原体已经进化到利用这一点，并使用唾液酸来“隐藏”自己，确保它们不被发现，或者作为一种释放病毒后代的机制。因此，针对 SA 和 ST 的抑制剂的开发提供了针对一系列疾病的机会。针对病毒、细菌或寄生虫酶的抑制剂可以直接针对其对人类的致病性。抗流感药物扎那米韦（Relenza™，葛兰素史克）和奥司他韦（达菲™，罗氏和吉利德）就是很好的例子，它们已在临床使用了二十多年。然而，对这些药物产生耐药性意味着持续需要新型有效且特异性的抑制剂。人类拥有 20 个 ST 和 4 个 SA，它们在细胞功能中发挥重要作用，但也与癌症进展有关，因为发现许多癌细胞上的聚糖高度唾液酸化。虽然 ST 与疾病之间的关系仍不清楚，但很明显，它们的特定抑制剂既可以作为工具，更好地了解其活性，又可以为开发抗癌药物奠定基础。在这里，我们回顾了针对病原体和人类的 SA 和 ST 抑制剂设计的最新进展。
Sialidases (SAs) and sialyltransferases (STs), the enzymes responsible for removing and adding sialic acid to other glycans, play essential roles in viruses, bacteria, parasites, and humans. Sialic acid is often the terminal sugar on glycans protruding from the cell surface in humans and is an important component for recognition and cell function. Pathogens have evolved to exploit this and use sialic acid to either “cloak” themselves, ensuring they remain undetected, or as a mechanism to enable release of virus progeny. The development of inhibitors against SAs and STs therefore provides the opportunity to target a range of diseases. Inhibitors targeting viral, bacterial, or parasitic enzymes can directly target their pathogenicity in humans. Excellent examples of this can be found with the anti-influenza drugs Zanamivir (Relenza™, GlaxoSmithKline) and Oseltamivir (Tamiflu™, Roche and Gilead), which have been used in the clinic for over two decades. However, the development of resistance against these drugs means there is an ongoing need for novel potent and specific inhibitors. Humans possess 20 STs and four SAs that play essential roles in cellular function, but have also been implicated in cancer progression, as glycans on many cancer cells are found to be hyper-sialylated. Whilst much remains unknown about how STs function in relation to disease, it is clear that specific inhibitors of them can serve both as tools to gain a better understanding of their activity and form the basis for development of anti-cancer drugs. Here we review the recent developments in the design of SA and ST inhibitors against pathogens and humans.