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.
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References
Adair JR (1992) Engineering antibodies for therapy. Immunol Rev 130:5–40
Angamuthu K, Piramanayagam S (2017) Evaluation of In silico protein secondary structure prediction methods by employing statistical techniques. Biomed Biotechnol Res J 1:29–36
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 105:9029–9034
Chodera JD, Mobley DL (2013) Entropy–enthalpy compensation: role and ramifications in biomolecular ligand recognition and design. Annu Rev Biophys 42:121–142
Constantinou A, Epenetos AA, Hreczuk-Hirst D, Jain S, Deonarain MP (2008) Modulation of antibody pharmacokinetics by chemical polysialylation. Bioconjug Chem 19:643–650
DeLano WL (2002) The PyMOL molecular graphics system. DeLano Scientific, San Carlos
Dimitrov A (2007) Ibalizumab, a CD4-specific mAb to inhibit HIV-1 infection. Curr Opin Investig Drugs 8:653–661
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
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
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):62–74
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
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 18:1632–1641
Hagihara Y, Saerens D (2012) Improvement of single domain antibody stability by disulfide bond introduction. Methods Mol Biol 911:399–416
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 53:450–457
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 3:479–486
Kuroda D, Shirai H, Jacobson MP, Nakamura H (2012) Computer-aided antibody design. Protein Eng Des Sel 25:507–521
Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51:2778–2786
Lippow SM, Wittrup KD, Tidor B (2007) Computational design of antibody-affinity improvement beyond in vivo maturation. Nat Biotechnol 25(10):1171–1176
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):3140–3149
Marvin JS, Lowman HB (2003) Redesigning an antibody fragment for faster association with its antigen. Biochemistry 42(23):7077–7083
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 24:447–454
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):1605–1612
Pierce BG, Hourai Y, Weng Z (2011) Accelerating protein docking in ZDOCK using an advanced 3D convolution library. PLoS ONE 6:e24657
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):1554–1557
Ritchie DW, Venkatraman V (2010) Ultra fast FFT protein docking on graphics processors. Bioinformatics 26:2398–2405
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–F38
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
Samish I, MacDermaid CM, Perez-Aguilar JM, Saven JG (2011) Theoretical and computational protein design. Annu Rev Phys Chem 62:129–149
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 84:6935–6942
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
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 1:49–54
Wyatt R, Sodroski J (1998) The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 280:1884–1888
Xu H, Littman DR (1993) A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell 74:633–643
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Tayebeh Farhadi, Atefeh Fakharian and Seyed MohammadReza Hashemian declare that they have no conflict of interest.
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Farhadi, T., Fakharian, A. & Hashemian, S.M. Affinity Improvement of a Humanized Antiviral Antibody by Structure-Based Computational Design. Int J Pept Res Ther 25, 181–186 (2019). https://doi.org/10.1007/s10989-017-9660-y
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DOI: https://doi.org/10.1007/s10989-017-9660-y