Zakas Philip M, Brown Harrison C, Knight Kristopher, Meeks Shannon L, Spencer H Trent, Gaucher Eric A, Doering Christopher B
Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, Georgia, USA.
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Nat Biotechnol. 2017 Jan;35(1):35-37. doi: 10.1038/nbt.3677. Epub 2016 Sep 26.
Optimization of a protein's pharmaceutical properties is usually carried out by rational design and/or directed evolution. Here we test an alternative approach based on ancestral sequence reconstruction. Using available genomic sequence data on coagulation factor VIII and predictive models of molecular evolution, we engineer protein variants with improved activity, stability, and biosynthesis potential and reduced inhibition by anti-drug antibodies. In principle, this approach can be applied to any protein drug based on a conserved gene sequence.
蛋白质药物特性的优化通常通过理性设计和/或定向进化来实现。在此，我们测试了一种基于祖先序列重建的替代方法。利用凝血因子VIII的现有基因组序列数据和分子进化预测模型，我们设计出了活性、稳定性和生物合成潜力得到改善且抗药抗体抑制作用降低的蛋白质变体。原则上，这种方法可应用于任何基于保守基因序列的蛋白质药物。
