Engineering an ACE2-Derived Fragment as a Decoy for Novel SARS-CoV-2 Virus.

Entry inhibitors are an important resource in the response against emerging pathogens like the novel SARS-CoV-2, which enters human cells via interaction between the surface spike glycoprotein and the cellular membrane receptor angiotensin-converting enzyme 2 (ACE2). Using a combination of comparative structural analyses of the binding surface of the spike to ACE2, docking experiments, and molecular dynamics simulations, we identified a stable fragment of ACE2 that binds to the spike, is soluble, and is not predicted to bind to its physiological ligand angiotensin II. From this fragment we computationally designed and experimentally validated a smaller, stable peptide that disrupts ACE2-spike interaction at nanomolar concentrations, suggesting its potential use as a decoy that could interfere with viral binding by competition.

[1]  D. Durden,et al.  Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection , 2022, Structure.

[2]  William F. Fadel,et al.  Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022 , 2022, MMWR. Morbidity and mortality weekly report.

[3]  P. Duerksen-Hughes,et al.  ACE2 : S1 RBD Interaction-Targeted Peptides and Small Molecules as Potential COVID-19 Therapeutics , 2021, Advances in pharmacological and pharmaceutical sciences.

[4]  P. A. Valiente,et al.  gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS. , 2021, Journal of chemical theory and computation.

[5]  Jung Hun Lee,et al.  Designing Short Peptides to Block the Interaction of SARS-CoV-2 and Human ACE2 for COVID-19 Therapeutics , 2021, Frontiers in Pharmacology.

[6]  Kam Y. J. Zhang,et al.  A Novel Therapeutic Peptide Blocks SARS-CoV-2 Spike Protein Binding with Host Cell ACE2 Receptor , 2021, Drugs in R&D.

[7]  P. Zielenkiewicz,et al.  Native Structure-Based Peptides as Potential Protein–Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor , 2021, Molecules.

[8]  O. Lequin,et al.  Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection , 2021, Communications Biology.

[9]  Pui-Kai Li,et al.  Rationally Designed ACE2-Derived Peptides Inhibit SARS-CoV-2. , 2020, Bioconjugate chemistry.

[10]  Veerendra Kumar,et al.  A potential peptide inhibitor of SARS-CoV-2 S and human ACE2 complex , 2020, Journal of biomolecular structure & dynamics.

[11]  C. Maranas,et al.  Computational biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity , 2020, Computational and Structural Biotechnology Journal.

[12]  Yang Zhang,et al.  De novo design of protein peptides to block association of the SARS-CoV-2 spike protein with human ACE2 , 2020, Aging.

[13]  Joseph M. Jacobson,et al.  Targeted intracellular degradation of SARS-CoV-2 via computationally optimized peptide fusions , 2020, bioRxiv.

[14]  Parth Sarthi Sen Gupta,et al.  ACE-2-Derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2 , 2020, Journal of proteome research.

[15]  Linqi Zhang,et al.  Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor , 2020, Nature.

[16]  K. Shi,et al.  Structural basis of receptor recognition by SARS-CoV-2 , 2020, Nature.

[17]  A. Walls,et al.  Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein , 2020, Cell.

[18]  H. Rothan,et al.  The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak , 2020, Journal of Autoimmunity.

[19]  William Sheffler,et al.  Efficient Flexible Backbone Protein-Protein Docking for Challenging Targets , 2017, bioRxiv.

[20]  Xinquan Wang,et al.  Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2 , 2018, PLoS pathogens.

[21]  Haixia Zhou,et al.  Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding , 2016, Cell Research.

[22]  Kumardeep Chaudhary,et al.  PEPstrMOD: structure prediction of peptides containing natural, non-natural and modified residues , 2015, Biology Direct.

[23]  Peter M. Kasson,et al.  GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit , 2013, Bioinform..

[24]  E. Sturrock,et al.  Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides , 2012, Scientific Reports.

[25]  G. Whittaker,et al.  Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein , 2012, Viruses.

[26]  Brian D. Weitzner,et al.  Benchmarking and Analysis of Protein Docking Performance in Rosetta v3.2 , 2011, PloS one.

[27]  Fang Li,et al.  Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor , 2009, Proceedings of the National Academy of Sciences.

[28]  L. Truong,et al.  Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. , 2008, The American journal of pathology.

[29]  Gajendra P.S. Raghava,et al.  PEPstr: a de novo method for tertiary structure prediction of small bioactive peptides. , 2007, Protein and peptide letters.

[30]  S. Harrison,et al.  Structure of SARS Coronavirus Spike Receptor-Binding Domain Complexed with Receptor , 2005, Science.

[31]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..