Glycosaminoglycans (GAGs) are very complex, natural anionic polysaccharides. They are polymers of repeating disaccharide units of uronic acid and hexosamine residues. Owing to their template-free, spatiotemporally-controlled, and enzyme-mediated biosyntheses, GAGs possess enormous polydispersity, heterogeneity, and structural diversity which often translate into multiple biological roles. It is well documented that GAGs contribute to physiological and pathological processes by binding to proteins including serine proteases, serpins, chemokines, growth factors, and microbial proteins. Despite advances in the GAG field, the GAG-protein interface remains largely unexploited by drug discovery programs. Thus, Non-Saccharide Glycosaminoglycan Mimetics (NSGMs) have been rationally developed as a novel class of sulfated molecules that modulate GAG-protein interface to promote various biological outcomes of substantial benefit to human health. In this review, we describe the chemical, biochemical, and pharmacological aspects of recently reported NSGMs and highlight their therapeutic potentials as structurally and mechanistically novel anti-coagulants, anti-cancer agents, anti-emphysema agents, and anti-viral agents. We also describe the challenges that complicate their advancement and describe ongoing efforts to overcome these challenges with the aim of advancing the novel platform of NSGMs to clinical use.

糖胺聚糖 (GAG) 是非常复杂的天然阴离子多糖。它们是糖醛酸和己糖胺残基的重复二糖单元的聚合物。由于其无模板、时空控制和酶介导的生物合成，GAG 具有巨大的多分散性、异质性和结构多样性，通常转化为多种生物学作用。有充分证据表明，GAG 通过与丝氨酸蛋白酶、丝氨酸蛋白酶抑制剂、趋化因子、生长因子和微生物蛋白等蛋白质结合来促进生理和病理过程。尽管 GAG 领域取得了进展，但药物发现项目在很大程度上仍未开发 GAG-蛋白质界面。因此，非糖糖胺聚糖模拟物 (NSGM) 已被合理开发为一类新型硫酸化分子，可调节 GAG-蛋白质界面，以促进对人类健康产生重大益处的各种生物学结果。在这篇综述中，我们描述了最近报道的 NSGM 的化学、生化和药理学方面，并强调了它们作为结构和机制上新型抗凝血剂、抗癌剂、抗肺气肿剂和抗病毒剂的治疗潜力。我们还描述了使其进展复杂化的挑战，并描述了克服这些挑战的持续努力，旨在将 NSGM 的新平台推向临床应用。