Techniques assisting peptide vaccine and peptidomimetic design. Sidechain exposure in the SARS-CoV-2 spike glycoprotein

The aim of the present study is to discuss the design of peptidomimetics against SARS-COV-2, to develop and apply a method of protein structure analysis that is particularly appropriate to applying and discussing such design, and also to use that method to summarize some important features of the SARS-COV-2 spike protein sequence. A tool for assessing sidechain exposure in the SARS-CoV-2 spike glycoprotein is described. It extends to assessing accessibility of sidechains by considering several different three-dimensional structure determinations of SARS-CoV-2 and SARS-CoV-1 spike protein. The method is designed to be insensitive to a distance limit for counting neighboring atoms and the results are in good agreement with the physical chemical properties and exposure trends of the 20 naturally occurring sidechains. The spike protein sequence is analyzed with comment regarding exposable character. It includes studies of complexes with antibody elements and ACE2. These indicate changes in exposure at sites remote to those at which the antibody binds. They are of interest concerning design of synthetic peptide vaccines, and for peptidomimetics as a basis of drug discovery. The method was also developed in order to provide linear (one-dimensional) information that can be used along with other bioinformatics data of this kind in data mining and machine learning, potentially as genomic data regarding protein polymorphisms to be combined with more traditional clinical data.

[1]  B. Robson,et al.  Bioinformatics studies on a function of the SARS-CoV-2 spike glycoprotein as the binding of host sialic acid glycans , 2020, Computers in Biology and Medicine.

[2]  Naveen Vankadari,et al.  Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26 , 2020, Emerging microbes & infections.

[3]  R. Penner.  Conserved High Free Energy Sites in Human Coronavirus Spike Glycoprotein Backbones , 2020, J. Comput. Biol..

[4]  Barry Robson,et al.  Introduction to proteins and protein engineering , 1986 .

[5]  Y. Al-Abed,et al.  Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics , 2020, Future medicinal chemistry.

[6]  D. Hamre,et al.  A New Virus Isolated from the Human Respiratory Tract.∗ , 1966, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[7]  E. Holmes,et al.  Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding , 2020, The Lancet.

[8]  Xifeng Lu,et al.  In silico design of antiviral peptides targeting the spike protein of SARS-CoV-2 , 2020, Peptides.

[9]  Eldon Emberly,et al.  Correlation between sequence hydrophobicity and surface‐exposure pattern of database proteins , 2003, Protein science : a publication of the Protein Society.

[10]  Pinak Chakrabarti,et al.  Quantifying the accessible surface area of protein residues in their local environment. , 2002, Protein engineering.

[11]  B. Robson.  Doppelgänger proteins as drug leads , 1996, Nature Biotechnology.

[12]  G. Herrler,et al.  SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor , 2020, Cell.

[13]  Xiaoxu Tian,et al.  Identification of 22 N-glycosites on spike glycoprotein of SARS-CoV-2 and accessible surface glycopeptide motifs: implications for vaccination and antibody therapeutics , 2020, Glycobiology.

[14]  B. Lee,et al.  The interpretation of protein structures: estimation of static accessibility. , 1971, Journal of molecular biology.

[15]  Barry Robson,et al.  PRO_LIGAND: An approach to de novo molecular design. 4. Application to the design of peptides , 1995, J. Comput. Aided Mol. Des..

[16]  V. Hruby,et al.  Peptidomimetics, a synthetic tool of drug discovery. , 2008, Current opinion in chemical biology.

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

[18]  M. V. Van Regenmortel,et al.  Antigenic mimicry of natural L-peptides with retro-inverso-peptidomimetics. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[19]  G. Whittaker,et al.  Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein , 2014, Proceedings of the National Academy of Sciences.

[20]  D. Tyrrell,et al.  Cultivation of viruses from a high proportion of patients with colds. , 1966, Lancet.

[21]  Zhènglì Shí,et al.  Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion , 2020, Cell Research.

[22]  S. Muller,et al.  D-peptides as immunogens and diagnostic reagents. , 1998, Current opinion in biotechnology.

[23]  L. Mabonga,et al.  Peptidomimetics: A Synthetic Tool for Inhibiting Protein–Protein Interactions in Cancer , 2019, International Journal of Peptide Research and Therapeutics.

[24]  Joanna Trylska,et al.  HIV-1 protease substrate binding and product release pathways explored with coarse-grained molecular dynamics. , 2007, Biophysical journal.

[25]  Mirror‐image Phage Display: Aiming at the Mirror , 2003, Chembiochem : a European journal of chemical biology.

[26]  B. Robson,et al.  COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles’ heel conserved region to minimize probability of escape mutations and drug resistance , 2020, Computers in Biology and Medicine.

[27]  J. Dubuisson,et al.  HCoV-229E spike protein fusion activation by trypsin-like serine proteases is mediated by proteolytic processing in the S2' region. , 2018, The Journal of general virology.

[28]  M. Hoffmann,et al.  A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells , 2020, Molecular Cell.

[29]  G. Whittaker,et al.  Structural modeling of 2019-novel coronavirus (nCoV) spike protein reveals a proteolytically-sensitive activation loop as a distinguishing feature compared to SARS-CoV and related SARS-like coronaviruses , 2020, bioRxiv.

[30]  B. Robson,et al.  Computers and viral diseases. Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus , 2020, Computers in Biology and Medicine.

[31]  B. Maiti.  Potential Role of Peptide-Based Antiviral Therapy Against SARS-CoV-2 Infection , 2020, ACS pharmacology & translational science.

[32]  V. Khavinson,et al.  Peptides: Prospects for Use in the Treatment of COVID-19 , 2020, Molecules.

[33]  K. Gotoh.  Radial Distribution Function , 2012 .

[34]  A. Trabocchi,et al.  Peptidomimetics in Organic and Medicinal Chemistry: The Art of Transforming Peptides in Drugs , 2014 .

[35]  D. E. Clark,et al.  PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores. , 1994, Journal of medicinal chemistry.

[36]  M. Sata,et al.  Assessment of synthetic peptides of severe acute respiratory syndrome coronavirus recognized by long‐lasting immunity , 2004, Tissue antigens.

[37]  Shibo Jiang,et al.  Identification of Immunodominant Sites on the Spike Protein of Severe Acute Respiratory Syndrome (SARS) Coronavirus: Implication for Developing SARS Diagnostics and Vaccines , 2004, The Journal of Immunology.

[38]  P. Masters,et al.  The Molecular Biology of Coronaviruses , 2006, Advances in Virus Research.

[39]  B. Robson,et al.  The use of knowledge management tools in viroinformatics. Example study of a highly conserved sequence motif in Nsp3 of SARS-CoV-2 as a therapeutic target , 2020, Computers in Biology and Medicine.

[40]  Xiaolei Yin,et al.  Identification of an Antigenic Determinant on the S2 Domain of the Severe Acute Respiratory Syndrome Coronavirus Spike Glycoprotein Capable of Inducing Neutralizing Antibodies , 2004, Journal of Virology.

[41]  Barry Robson,et al.  Extension of the Quantum Universal Exchange Language to precision medicine and drug lead discovery. Preliminary example studies using the mitochondrial genome , 2020, Comput. Biol. Medicine.