Department of Chemical Engineering, University of Washington, Seattle, Washington, WA 98195, USA.
Nat Chem. 2011 Dec 11;4(1):59-63. doi: 10.1038/nchem.1213.
Treatment with therapeutic proteins is an attractive approach to targeting a number of challenging diseases. Unfortunately, the native proteins themselves are often unstable in physiological conditions, reducing bioavailability and therefore increasing the dose that is required. Conjugation with poly(ethylene glycol) (PEG) is often used to increase stability, but this has a detrimental effect on bioactivity. Here, we introduce conjugation with zwitterionic polymers such as poly(carboxybetaine). We show that poly(carboxybetaine) conjugation improves stability in a manner similar to PEGylation, but that the new conjugates retain or even improve the binding affinity as a result of enhanced protein-substrate hydrophobic interactions. This chemistry opens a new avenue for the development of protein therapeutics by avoiding the need to compromise between stability and affinity.
治疗性蛋白的治疗方法是针对许多具有挑战性的疾病的一种有吸引力的方法。不幸的是，天然蛋白本身在生理条件下往往不稳定，降低了生物利用度，因此增加了所需的剂量。与聚乙二醇（PEG）的缀合通常用于增加稳定性，但这对生物活性有不利影响。在这里，我们引入了与两性离子聚合物如聚（羧基甜菜碱）的缀合。我们表明，聚（羧基甜菜碱）缀合以类似于 PEGylation 的方式提高了稳定性，但由于增强的蛋白质-底物疏水性相互作用，新的缀合物保留甚至提高了结合亲和力。这种化学方法通过避免在稳定性和亲和力之间进行妥协，为开发蛋白质治疗药物开辟了新的途径。
