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Affinity Improvement of a Humanized Antiviral Antibody by Structure-Based Computational Design

  • Tayebeh Farhadi
  • Atefeh Fakharian
  • Seyed MohammadReza HashemianEmail author
Article

Abstract

Acquired immune deficiency syndrome (AIDS) is one of the most lethal infectious diseases influencing human community. While fusion of HIV-1 and host cell membranes, viral envelope glycoprotein gp120 is dissociated and a cascade of refolding events is initiated in the viral fusion protein gp41. To promote formation of the co-receptor binding site on the gp120 and initial attachment, HIV-1 employs CD4 as its primary receptor. Ibalizumab, a humanized, anti-CD4 monoclonal antibody for HIV-1 infection, was investigated in silico to design a potential improved antibody. Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Here, crystal structure of CD4 along with monoclonal antibody Ibalizumab was explored. Thr30, Ser31, Asn52, Tyr53, Asn98 and Tyr99 in heavy chain of Ibalizumab were mutated with 19 standard amino acid residues using computational methods. A set of 720 mutant macromolecules were designed, and binding affinity of these macromolecules to CD4 was evaluated through Ag-Ab docking, binding free-energy calculations, and hydrogen binding estimation. In comparison to Ibalizumab, seven designed theoretical antibody demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential antibodies to serve as therapeutic options for HIV infection.

Keywords

Computer-aided antibody engineering Affinity improvement Ibalizumab 

Notes

Compliance with Ethical Standards

Conflict of interest

Tayebeh Farhadi, Atefeh Fakharian and Seyed MohammadReza Hashemian declare that they have no conflict of interest.

Research involving with Human and Animal Rights

This article does not contain any studies with human or animal subject performed by the author.

Supplementary material

10989_2017_9660_MOESM1_ESM.docx (2.2 mb)
Supplementary material 1 (DOCX 2252 KB)

References

  1. Adair JR (1992) Engineering antibodies for therapy. Immunol Rev 130:5–40CrossRefGoogle Scholar
  2. Angamuthu K, Piramanayagam S (2017) Evaluation of In silico protein secondary structure prediction methods by employing statistical techniques. Biomed Biotechnol Res J 1:29–36CrossRefGoogle Scholar
  3. Barderas R, Desmet J, Timmerman P, Meloen R, Casal JI (2008) Affinity maturation of antibodies assisted by in silico modeling. Proc Natl Acad Sci USA 105:9029–9034CrossRefGoogle Scholar
  4. Chodera JD, Mobley DL (2013) Entropy–enthalpy compensation: role and ramifications in biomolecular ligand recognition and design. Annu Rev Biophys 42:121–142CrossRefGoogle Scholar
  5. Constantinou A, Epenetos AA, Hreczuk-Hirst D, Jain S, Deonarain MP (2008) Modulation of antibody pharmacokinetics by chemical polysialylation. Bioconjug Chem 19:643–650CrossRefGoogle Scholar
  6. DeLano WL (2002) The PyMOL molecular graphics system. DeLano Scientific, San CarlosGoogle Scholar
  7. Dimitrov A (2007) Ibalizumab, a CD4-specific mAb to inhibit HIV-1 infection. Curr Opin Investig Drugs 8:653–661Google Scholar
  8. Farhadi T (2017) In silico designing of peptide inhibitors against pregnane X receptor: the novel candidates to control drug metabolism. Int J Pept Res Ther.  https://doi.org/10.1007/s10989-017-9627-z Google Scholar
  9. Farhadi T, Hashemian SMR (2017) Constructing novel chimeric DNA vaccine against Salmonella enterica based on SopB and GroEL proteins: an in silico approach. J Pharm Investig.  https://doi.org/10.1007/s40005-017-0360-6 Google Scholar
  10. Farhadi T, Nezafat N, Ghasemi Y (2015) In silico phylogenetic analysis of Vibrio cholera isolates based on three housekeeping genes. Int J Comput Biol Drug Des 8(1):62–74CrossRefGoogle Scholar
  11. Farhadi T, Fakharian A, Ovchinnikov RS (2017) Virtual screening for potential inhibitors CTX-M-15 Protein of Klebsiella pneumonia. Interdiscip Sci Comput Life Sci.  https://doi.org/10.1007/s12539-017-0222-y Google Scholar
  12. Freeman MM, Seaman MS, Rits-Volloch S, Hong X, Kao CY, Ho DD, Chen B (2010) Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody. Structure 18:1632–1641CrossRefGoogle Scholar
  13. Hagihara Y, Saerens D (2012) Improvement of single domain antibody stability by disulfide bond introduction. Methods Mol Biol 911:399–416Google Scholar
  14. Jacobson JM, Kuritzkes DR, Godofsky E, DeJesus E, Larson JA, Weinheimer SP, Lewis ST (2009) Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti- CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother 53:450–457CrossRefGoogle Scholar
  15. Kawa S, Onda M, Ho M, Kreitman RJ, Bera TK et al (2011) The improvement of an anti-CD22 immunotoxin: conversion to single-chain and disulfide stabilized form and affinity maturation by alanine scan. MAbs 3:479–486CrossRefGoogle Scholar
  16. Kuroda D, Shirai H, Jacobson MP, Nakamura H (2012) Computer-aided antibody design. Protein Eng Des Sel 25:507–521CrossRefGoogle Scholar
  17. Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51:2778–2786CrossRefGoogle Scholar
  18. Lippow SM, Wittrup KD, Tidor B (2007) Computational design of antibody-affinity improvement beyond in vivo maturation. Nat Biotechnol 25(10):1171–1176CrossRefGoogle Scholar
  19. London N, Raveh B, Movshovitz-Attias D, Schueler-Furman O (2010) Can self-inhibitory peptides be derived from the interfaces of globular protein-protein interactions? Proteins 78(15):3140–3149CrossRefGoogle Scholar
  20. Marvin JS, Lowman HB (2003) Redesigning an antibody fragment for faster association with its antigen. Biochemistry 42(23):7077–7083Google Scholar
  21. Muda M, Gross AW, Dawson JP, He C, Kurosawa E et al (2011) Therapeutic assessment of SEED: a new engineered antibody platform designed to generate mono- and bispecific antibodies. Protein Eng Des Sel 24:447–454CrossRefGoogle Scholar
  22. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612CrossRefGoogle Scholar
  23. Pierce BG, Hourai Y, Weng Z (2011) Accelerating protein docking in ZDOCK using an advanced 3D convolution library. PLoS ONE 6:e24657CrossRefGoogle Scholar
  24. Popper SJ, Sarr AD, Gueye-Ndiaye A, Mboup S, Essex ME, Kanki PJ (2000) Low plasma human immunodeficiency virus type 2 viral load is independent of proviral load: low virus production in vivo. J Virol 74(3):1554–1557CrossRefGoogle Scholar
  25. Ritchie DW, Venkatraman V (2010) Ultra fast FFT protein docking on graphics processors. Bioinformatics 26:2398–2405CrossRefGoogle Scholar
  26. Rosok BI, Bostad L, Voltersvik P, Bjerknes R, Olofsson J, Asjo B et al (1996) Reduced CD4 cell counts in blood do not reflect CD4 cell depletion in tonsillar tissue in asymptomatic HIV-1 infection. AIDS 10(10):F35–F38Google Scholar
  27. Roy A, Nair S, Sen N, Soni N, Madhusudhan MS (2017) In silico methods for design of biological therapeutics. Methods.  https://doi.org/10.1016/j.ymeth.2017.09.008 Google Scholar
  28. Samish I, MacDermaid CM, Perez-Aguilar JM, Saven JG (2011) Theoretical and computational protein design. Annu Rev Phys Chem 62:129–149CrossRefGoogle Scholar
  29. Song R, Franco D, Kao CY, Yu F, Huang Y, Ho DD (2010) Epitope mapping of Ibalizumab, a humanized anti-CD4 monoclonal antibody with anti-HIV-1 activity in infected patients. J Virol 84:6935–6942CrossRefGoogle Scholar
  30. Vidya-Vijayan KK, Karthigeyan KP, Tripathi SP, Hanna LE (2017) Pathophysiology of CD4+ T-cell depletion in HIV-1 and HIV-2 infections. Front Immunol 8:580.  https://doi.org/10.3389/fimmu.2017.00580 CrossRefGoogle Scholar
  31. Wankhade G, Kamble S, Deshmukh S, Jena L, Waghmare P, Harinath BC (2017) Inhibition of mycobacterial CYP125 enzyme by sesamin and β-sitosterol: an in silico and in vitro study. Biomed Biotechnol Res J 1:49–54CrossRefGoogle Scholar
  32. Wyatt R, Sodroski J (1998) The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 280:1884–1888CrossRefGoogle Scholar
  33. Xu H, Littman DR (1993) A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell 74:633–643CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Tayebeh Farhadi
    • 1
  • Atefeh Fakharian
    • 1
  • Seyed MohammadReza Hashemian
    • 1
    Email author
  1. 1.Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD)Shahid Beheshti University of Medical SciencesTehranIran

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