Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia 23219, United States.
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
J Med Chem. 2023 Apr 13;66(7):4503-4531. doi: 10.1021/acs.jmedchem.3c00132. Epub 2023 Mar 31.
Natural glycosaminoglycans (GAGs) are arguably the most diverse collection of natural products. Unfortunately, this bounty of structures remains untapped. Decades of research has realized only one GAG-like synthetic, small-molecule drug, fondaparinux. This represents an abysmal output because GAGs present a frontier that few medicinal chemists, and even fewer pharmaceutical companies, dare to undertake. GAGs are heterogeneous, polymeric, polydisperse, highly water soluble, synthetically challenging, too rapidly cleared, and difficult to analyze. Additionally, GAG binding to proteins is not very selective and GAG-binding sites are shallow. This Perspective attempts to transform this negative view into a much more promising one by highlighting recent advances in GAG mimetics. The Perspective focuses on the principles used in the design/discovery of drug-like, synthetic, sulfated small molecules as allosteric modulators of coagulation factors, such as antithrombin, thrombin, and factor XIa. These principles will also aid the design/discovery of sulfated agents against cancer, inflammation, and microbial infection.
天然糖胺聚糖（GAGs）可以说是最具多样性的天然产物集合。不幸的是，这些结构仍然未被开发。数十年来的研究只实现了一种类似 GAG 的合成小分子药物，即磺达肝素。这代表着产出非常惨淡，因为 GAGs 代表了一个前沿领域，很少有药物化学家，甚至更少的制药公司敢于涉足。GAGs 是异质的、聚合的、多分散的、高度水溶性的、合成具有挑战性的、清除速度过快的，并且难以分析。此外，GAG 与蛋白质的结合不是很有选择性，GAG 结合位点较浅。本文通过强调 GAG 模拟物的最新进展，试图将这种负面观点转变为更有前途的观点。本文重点介绍了设计/发现类药物、合成、硫酸化小分子作为抗凝血酶、凝血酶和因子 Xa 等凝血因子的变构调节剂的原理。这些原则也将有助于设计/发现针对癌症、炎症和微生物感染的硫酸化药物。
