美国华盛顿大学David Baker课题组从头设计出SARS-CoV-2的小蛋白抑制剂。相关论文于2020年9月9日在线发表于国际学术期刊《科学》。

Author: Longxing Cao, Inna Goreshnik, Brian Coventry, James Brett Case, Lauren Miller, Lisa Kozodoy, Rita E. Chen, Lauren Carter, Alexandra C. Walls, Young-Jun Park, Eva-Maria Strauch, Lance Stewart, Michael S. Diamond, David Veesler, David Baker

Issue&Volume: 2020/09/09

Abstract: Abstract Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with the Spike receptor binding domain (RBD), or docked against the RBD to identify new binding modes, and their amino acid sequences designed to optimize target binding, folding and stability. Ten designs bound the RBD with affinities ranging from 100pM to 10nM, and blocked  ARS-CoV-2 infection of Vero E6 cells with IC 50 values between 24 pM and 35 nM; The most potent, with new binding modes, are 56 and 64 residue proteins (IC 50 ~ 0.16 ng/ml). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.

DOI: 10.1126/science.abd9909

Source: https://science.sciencemag.org/content/early/2020/09/08/science.abd9909