The increasing availability of detailed structural information on many biological systems provides an avenue for manipulation of these structures, either for probing mechanism or for developing novel therapeutic agents for treating disease. This has been accompanied by the advent of several powerful new methods, such as the ability to incorporate non-natural amino acids or perform fragment screening, increasing the capacity to leverage this new structural information to aid in these pursuits. The abundance of structural information also provides new opportunities for protein engineering, which may become more and more relevant as treatment of diseases using gene therapy approaches become increasingly common. This is illustrated by example with the TGF-β family of proteins, for which there is ample structural information, yet no approved inhibitors for treating diseases, such as cancer and fibrosis that are promoted by excessive TGF-β signaling. The results presented demonstrate that through several relatively simple modifications, primarily involving the removal of an α-helix and replacement of it with a flexible loop, it is possible to alter TGF-βs from being potent signaling proteins into inhibitors of TGF-β signaling. The engineered TGF-βs have improved specificity relative to kinase inhibitors and a much smaller size compared to monoclonal antibodies, and thus may prove successful as either as an injected therapeutic or as a gene therapy-based therapeutic, where other classes of inhibitors have failed.

许多生物系统上详细结构信息的可用性不断提高，为操纵这些结构提供了一条途径，无论是探测机制还是开发用于治疗疾病的新型治疗剂。随之而来的是一些强大的新方法的问世，例如掺入非天然氨基酸或进行片段筛选的能力，提高了利用这种新的结构信息来辅助这些追求的能力。丰富的结构信息也为蛋白质工程提供了新的机会，随着使用基因治疗方法治疗疾病变得越来越普遍，蛋白质工程可能变得越来越重要。以TGF-β蛋白质家族为例对此进行了说明，该家族具有足够的结构信息，尚无批准的用于治疗疾病的抑制剂，这些疾病是由过度的TGF-β信号传导促进的，例如癌症和纤维化。呈现的结果表明，通过几种相对简单的修饰，主要包括去除α-螺旋并用柔性环取代，可以将TGF-β从有效的信号蛋白转变为TGF-β信号的抑制剂。相对于激酶抑制剂，改造的TGF-β具有更高的特异性，并且与单克隆抗体相比，其尺寸要小得多，因此可以证明是成功的注射疗法或基于基因疗法的疗法，而其他类型的抑制剂却失败了。提出的结果表明，通过几种相对简单的修饰，主要包括去除α-螺旋并用柔性环取代，可以将TGF-β从有效的信号蛋白转变为TGF-β信号的抑制剂。相对于激酶抑制剂，改造的TGF-β具有更高的特异性，并且与单克隆抗体相比，其尺寸要小得多，因此，无论是作为注射治疗剂还是基于基因治疗剂的治疗剂，在其他类型的抑制剂均无法发挥作用的情况下，都可以证明是成功的。提出的结果表明，通过几种相对简单的修饰，主要包括去除α-螺旋并用柔性环取代，可以将TGF-β从有效的信号蛋白转变为TGF-β信号的抑制剂。相对于激酶抑制剂，改造的TGF-β具有更高的特异性，并且与单克隆抗体相比，其尺寸要小得多，因此，无论是作为注射治疗剂还是基于基因治疗剂的治疗剂，在其他类型的抑制剂均无法发挥作用的情况下，都可以证明是成功的。