Centre for Advanced Macromolecular Design, School of Chemistry, UNSW Sydney, Kensington, NSW 2052, Australia.
School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
J Am Chem Soc. 2024 Aug 7;146(31):22093-22102. doi: 10.1021/jacs.4c08658. Epub 2024 Jul 26.
Here we introduce amphiphilic star polymers as versatile protein mimics capable of approximating the activity of certain native proteins. Our study focuses on designing a synthetic polymer capable of replicating the biological activity of TRAIL, a promising anticancer protein that shows very poor circulation half-life. Successful protein mimicry requires precise control over the presentation of receptor-binding peptides from the periphery of the polymer scaffold while maintaining enough flexibility for protein-peptide binding. We show that this can be achieved by building hydrophobic blocks into the core of a star-shaped polymer, which drives unimolecular collapse in water. By screening a library of diblock copolymer stars, we were able to design structures with IC's of ∼4 nM against a colon cancer cell line (COLO205), closely approximating the activity of the native TRAIL protein. This finding highlights the broad potential for simple synthetic polymers to mimic the biological activity of complex proteins.
在这里，我们介绍两亲性星形聚合物作为多功能的蛋白质模拟物，能够近似某些天然蛋白质的活性。我们的研究重点是设计一种能够复制 TRAIL 生物活性的合成聚合物，TRAIL 是一种很有前途的抗癌蛋白，但它的循环半衰期非常短。成功的蛋白质模拟需要精确控制聚合物支架外围的受体结合肽的呈现，同时保持足够的蛋白质-肽结合灵活性。我们表明，这可以通过在星形聚合物的核心构建疏水性块来实现，这会导致在水中发生单分子塌陷。通过筛选嵌段共聚物星形聚合物文库，我们能够设计出针对结肠癌细胞系（COLO205）的 IC50 约为 4 nM 的结构，这与天然 TRAIL 蛋白的活性非常接近。这一发现突显了简单的合成聚合物在模拟复杂蛋白质的生物学活性方面的广泛潜力。
