Protein Science Laboratory, Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.
J Thromb Haemost. 2011 Jul;9 Suppl 1:195-208. doi: 10.1111/j.1538-7836.2011.04279.x.
Exogenous factors isolated from venoms of snakes and saliva of haematophagous animals that affect thrombosis and haemostasis have contributed significantly to the development of diagnostic agents, research tools and life-saving drugs. Here, I discuss recent advances in the discovery, structural and functional characterisation, and mechanism of action of new procoagulant and anti-haemostatic proteins. In nature, these factors have evolved to target crucial 'bottlenecks' in the coagulation cascade and platelet aggregation. Several simple protein scaffolds are used to target a wide variety of target proteins and receptors exhibiting functional divergence. Different protein scaffolds have also evolved to target identical, physiologically relevant key enzymes or receptors exhibiting functional convergence. At times, exogenous factors bind to the same target protein, but at distinct sites, to differentially attenuate their functions exhibiting mechanistic divergence within the same family of proteins. The structure-function relationships of these factors are subtle and complicated but represent an exciting challenge. These studies provide ample opportunities to design highly specific and precise ligands to achieve desired biological target function. Although only a small number of them have been characterised to date, the molecular and mechanical diversities of these exogenous factors and their contributions to understanding molecular and cellular events in thrombosis and haemostasis as well as developing diagnostic and research tools and therapeutic agents, is outstanding. Based on the current status, I have attempted to identify future potential and prospects in this area of research.
从蛇毒和吸血动物唾液中分离出的影响血栓形成和止血的外源因子，为诊断试剂、研究工具和救生药物的开发做出了重大贡献。在这里，我讨论了新型促凝和抗止血蛋白的发现、结构和功能特征以及作用机制的最新进展。在自然界中，这些因子的进化是为了针对凝血级联和血小板聚集的关键“瓶颈”。几种简单的蛋白质支架被用来针对表现出功能分歧的广泛的靶蛋白和受体。不同的蛋白质支架也进化为针对相同的、生理相关的关键酶或受体，表现出功能趋同。有时，外源因子结合到相同的靶蛋白上，但结合在不同的部位，以不同的方式削弱其功能，在同一蛋白家族中表现出机制上的差异。这些因子的结构-功能关系微妙而复杂，但却是一个令人兴奋的挑战。这些研究为设计高度特异性和精确的配体以实现所需的生物靶功能提供了充足的机会。尽管迄今为止只有少数几种得到了表征，但这些外源因子的分子和机械多样性及其对理解血栓形成和止血中分子和细胞事件以及开发诊断和研究工具以及治疗剂的贡献是卓越的。基于目前的状况，我试图确定该研究领域未来的潜力和前景。
