Elevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans may inhibit MMP-8 because natural glycosaminoglycans are known to modulate the functions of various MMPs. The screening a library of 58 synthetic, sulfated mimetics consisting of a dozen scaffolds led to the identification of only two scaffolds, including sulfated benzofurans and sulfated quinazolinones, as promising inhibitors of MMP-8. Interestingly, the sulfated quinazolinones displayed full antagonism of MMP-8 and sulfated benzofuran appeared to show partial antagonism. Of the two, sulfated quinazolinones exhibited a >10-fold selectivity for MMP-8 over MMP-9, a closely related metalloproteinase. Molecular modeling suggested the plausible occupancy of the S₁^′ pocket on MMP-8 as the distinguishing feature of the interaction. Overall, this work provides the first proof that the sulfated mimetics of glycosaminoglycans could lead to potent, selective, and catalytic activity-tunable, small molecular inhibitors of MMP-8.

中文翻译：

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基质金属蛋白酶8的硫酸化小分子抑制剂的发现。

基质金属蛋白酶8（MMP-8）活性升高是许多疾病的病因，包括动脉粥样硬化，肺纤维化和败血症。然而，几乎没有发现MMP-8的小分子抑制剂。我们认为，糖胺聚糖的合成非糖模拟物可能抑制MMP-8，因为已知天然糖胺聚糖可以调节各种MMP的功能。筛选了由十二个支架组成的58个合成的，硫酸盐模拟物的文库，导致仅鉴定了两个支架，包括硫酸化苯并呋喃和硫酸化喹唑啉酮，它们是有希望的MMP-8抑制剂。有趣的是，硫酸化的喹唑啉酮显示出对MMP-8的完全拮抗作用，而硫酸化的苯并呋喃似乎显示出部分拮抗作用。在这两种硫酸化的喹唑啉酮中，> MMP-8的选择性是密切相关的金属蛋白酶MMP-9的10倍。分子建模表明S的合理占据MMP-8上的₁ ^'口袋是相互作用的显着特征。总的来说，这项工作提供了第一个证明，即糖胺聚糖的硫酸盐模拟物可能导致有效，选择性和催化活性可调的MMP-8小分子抑制剂。