McNiff Michaela L, Chadwick Jennifer S
Department of Pharmaceutical Chemistry, University of Kansas, 2093 Constant Ave, Lawrence, KS 66047.
Department of Pharmaceutical Chemistry, University of Kansas, 2093 Constant Ave, Lawrence, KS 66047.
Protein Eng Des Sel. 2017 Jun 1;30(6):467-475. doi: 10.1093/protein/gzx030.
Biologics can be an improvement to small molecule drugs, providing high specificity for an identified target, lowering toxicity and limiting side effects. To achieve effective delivery, the biologic must have sufficient time to reach the target tissue. A prolonged half-life in the circulating environment is desired, but often serum stability is limited by proteases. Proteolysis in the serum causes degradation and inactivation as the biologic is fragmented and more rapidly cleared from the body. To improve the circulating half-life, large, hydrophilic polymers may be conjugated or stable fusion tags may be engineered to increase the effective size of the peptide and to hinder degradation by proteases. Improved resistance to proteases is essential for effective delivery. Here, a proof of concept study is presented using a metal-binding tripeptide tag known as the claMP Tag to create an inline conjugate and the ability of the tag to inhibit proteolysis was examined.
生物制剂可能是小分子药物的一种改进,它对已确定的靶点具有高特异性,能降低毒性并限制副作用。为实现有效递送,生物制剂必须有足够时间到达靶组织。人们期望其在循环环境中的半衰期延长,但血清稳定性常受蛋白酶限制。血清中的蛋白水解作用会导致生物制剂降解和失活,因为其会被碎片化并更快地从体内清除。为提高循环半衰期,可连接大型亲水性聚合物或设计稳定的融合标签,以增加肽的有效大小并阻碍蛋白酶降解。对蛋白酶的抗性提高对于有效递送至关重要。在此,展示了一项概念验证研究,该研究使用一种名为claMP标签的金属结合三肽标签来创建一种内联缀合物,并检测了该标签抑制蛋白水解的能力。