COVID-19 Research Paper Volume 12, Issue 12 pp 11263—11276

De novo design of protein peptides to block association of the SARS-CoV-2 spike protein with human ACE2

Xiaoqiang Huang1, , Robin Pearce1, , Yang Zhang1,2, ,

  • 1 Department of Computational Medicine and Bioinformatics, Ann Arbor, MI 48109, USA
  • 2 Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA

Received: April 21, 2020       Accepted: May 25, 2020       Published: June 16, 2020
How to Cite

Copyright © 2020 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The outbreak of COVID-19 has now become a global pandemic that has severely impacted lives and economic stability. There is, however, no effective antiviral drug that can be used to treat COVID-19 to date. Built on the fact that SARS-CoV-2 initiates its entry into human cells by the receptor binding domain (RBD) of its spike protein binding to the angiotensin-converting enzyme 2 (hACE2), we extended a recently developed approach, EvoDesign, to design multiple peptide sequences that can competitively bind to the SARS-CoV-2 RBD to inhibit the virus from entering human cells. The protocol starts with the construction of a hybrid peptidic scaffold by linking two fragments grafted from the interface of the hACE2 protein (a.a. 22-44 and 351-357) with a linker glycine, which is followed by the redesign and refinement simulations of the peptide sequence to optimize its binding affinity to the interface of the SARS-CoV-2 RBD. The binding experiment analyses showed that the designed peptides exhibited a significantly stronger binding potency to hACE2 than the wild-type hACE2 receptor (with -53.35 vs. -46.46 EvoEF2 energy unit scores for the top designed and wild-type peptides, respectively). This study demonstrates a new avenue to utilize computationally designed peptide motifs to treat the COVID-19 disease by blocking the critical spike-RBD and hACE2 interactions.


ACE2: angiotensin-converting enzyme 2; COVID-19: coronavirus disease 2019; Cryo-EM: cryogenic electron microscopy; EEU: EvoEF2 energy unit; hACE2: human angiotensin-converting enzyme 2; MSA: multiple sequence alignment; NIL: non-redundant interface library; PDB: protein data bank; PPI: protein-protein interaction; PSSM: position-specific scoring matrix; RBD: receptor binding domain; RBM: receptor binding motif; SAMC: simulated annealing Monte Carlo; SARS-CoV: severe acute respiratory syndrome coronavirus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.