Mohamed Shifaza, Coombe Deirdre R
School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth 6102, Western Australia.
School of Applied Chemistry, Faculty of Science and Engineering, Curtin University, Perth 6102, Western Australia.
Pharmaceuticals (Basel). 2017 Oct 2;10(4):78. doi: 10.3390/ph10040078.
Heparin mimetics are synthetic and semi-synthetic compounds that are highly sulfated, structurally distinct analogues of glycosaminoglycans. These mimetics are often rationally designed to increase potency and binding selectivity towards specific proteins involved in disease manifestations. Some of the major therapeutic arenas towards which heparin mimetics are targeted include: coagulation and thrombosis, cancers, and inflammatory diseases. Although Fondaparinux, a rationally designed heparin mimetic, is now approved for prophylaxis and treatment of venous thromboembolism, the search for novel anticoagulant heparin mimetics with increased affinity and fewer side effects remains a subject of research. However, increasingly, research is focusing on the non-anticoagulant activities of these molecules. Heparin mimetics have potential as anti-cancer agents due to their ability to: (1) inhibit heparanase, an endoglycosidase which facilitates the spread of tumor cells; and (2) inhibit angiogenesis by binding to growth factors. The heparin mimetic, PI-88 is in clinical trials for post-surgical hepatocellular carcinoma and advanced melanoma. The anti-inflammatory properties of heparin mimetics have primarily been attributed to their ability to interact with: complement system proteins, selectins and chemokines; each of which function differently to facilitate inflammation. The efficacy of low/non-anticoagulant heparin mimetics in animal models of different inflammatory diseases has been demonstrated. These findings, plus clinical data that indicates heparin has anti-inflammatory activity, will raise the momentum for developing heparin mimetics as a new class of therapeutic agent for inflammatory diseases.
肝素模拟物是高度硫酸化的合成和半合成化合物，是结构独特的糖胺聚糖类似物。这些模拟物通常经过合理设计，以提高对参与疾病表现的特定蛋白质的效力和结合选择性。肝素模拟物的一些主要治疗领域包括：凝血和血栓形成、癌症和炎症性疾病。尽管合理设计的肝素模拟物磺达肝癸钠现已被批准用于预防和治疗静脉血栓栓塞，但寻找具有更高亲和力和更少副作用的新型抗凝肝素模拟物仍是一个研究课题。然而，越来越多的研究正聚焦于这些分子的非抗凝活性。肝素模拟物因其能够：（1）抑制乙酰肝素酶（一种促进肿瘤细胞扩散的内切糖苷酶）；以及（2）通过与生长因子结合来抑制血管生成，而具有作为抗癌药物的潜力。肝素模拟物PI - 88正在进行针对术后肝细胞癌和晚期黑色素瘤的临床试验。肝素模拟物的抗炎特性主要归因于它们与以下物质相互作用的能力：补体系统蛋白、选择素和趋化因子；它们各自发挥不同作用以促进炎症。低/非抗凝肝素模拟物在不同炎症性疾病动物模型中的疗效已得到证实。这些发现，加上表明肝素具有抗炎活性的临床数据，将推动开发肝素模拟物作为一类新型炎症性疾病治疗药物的势头。
