蛋白质设计算法可实现精准靶向细胞表面抗原

作者：王韵壹、李英、熊慧卿

本期文章：《科学》：Online/在线发表

美国华盛顿大学David Baker小组在研究中取得进展。他们的论文通过设计蛋白质合成可实现精确靶向细胞表面抗原。该研究于2020年8月20日发表于国际学术期刊《科学》。

研究人员设计了执行“与”、“或”和“非”布尔逻辑运算的共定位依赖蛋白转换器（Co-LOCKR）。仅当满足所有条件时，这些转换器才会通过构象变化激活，从而在复杂细胞群体中以单细胞分辨率快速生成转录非依赖的反应。研究人员利用AND门实现了T细胞对表达两种表面抗原肿瘤细胞的特异性，同时避免脱靶识别单抗原细胞；添加NOT或OR程序的3输入转换器以避免或包括表达第三种抗原的细胞。

因此，从头设计蛋白质可以对细胞表面抗原进行运算以实现将多个不同的结合互作整合到单个输出中。

据介绍，细胞的精准靶向具有一定挑战性，这是因为大多数哺乳动物细胞缺乏将它们与其他细胞区分开的单一细胞表面标记。一种解决该难题的方法是基于存在其表面蛋白质的特定组合来靶向细胞。

附：英文原文

Title: Designed protein logic to target cells with precise combinations of surface antigens

Author: Marc J. Lajoie, Scott E. Boyken, Alexander I. Salter, Jilliane Bruffey, Anusha Rajan, Robert A. Langan, Audrey Olshefsky, Vishaka Muhunthan, Matthew J. Bick, Mesfin Gewe, Alfredo Quijano-Rubio, JayLee Johnson, Garreck Lenz, Alisha Nguyen, Suzie Pun, Colin E. Correnti, Stanley R. Riddell, David Baker

Issue&Volume: 2020/08/20

Abstract: Abstract Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells based on specific combinations of proteins present on their surfaces. We design colocalization-dependent protein switches (Co-LOCKR) that perform AND, OR, and NOT Boolean logic operations. These switches activate through a conformational change only when all conditions are met, generating rapid, transcription-independent responses at single-cell resolution within complex cell populations. We implement AND gates to redirect T cell specificity against tumor cells expressing two surface antigens while avoiding off-target recognition of single-antigen cells, and 3-input switches that add NOT or OR logic to avoid or include cells expressing a third antigen. Thus, de novo designed proteins can perform computations on the surface of cells, integrating multiple distinct binding interactions into a single output.

DOI: 10.1126/science.aba6527

Source: https://science.sciencemag.org/content/early/2020/08/19/science.aba6527

期刊信息

Science：《科学》，创刊于1880年。隶属于美国科学促进会，最新IF：41.037

官方网址：https://www.sciencemag.org/