Skip to main content
SpringerLink
Log in

Conjugated Recombinant Proteins as Emerging New Drugs

  • Chapter
  • First Online:
Bioeconomy for Sustainable Development

  • 1037 Accesses

Abstract

Conjugation combines protein domains to achieve new functionalities in therapeutic drugs by utilizing their functional and structural versatility creating highly diverse macromolecules. Several human recombinant protein drugs are being used for the treatment of different diseases. However to improve these recombinant protein drugs’ bioavailability and to incorporate different new features in the single-protein drug, sortase-mediated conjugation is a promising technology. The sortase A enzyme from Staphylococcus aureus can link any two proteins if one contains N-terminal triglycine (GGG) motif and second contains C-terminal LPXTG motif. In this new protein recombinant drugs can be developed. It is estimated that in the future, conventional recombinant protein drugs will be modified with the help of conjugation technology, and new recombinant drugs will be available with further enhancement of recombinant drugs business worldwide.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abuchowski A, van Es T, Palczuk N, Davis F (1977) Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J Biol Chem 252:3578–3581

    CAS  Google Scholar 

  • Aggarwal S (2011) What’s fueling the biotech engine. 2010 to 2011. Nat Biotech 29:1083–1089

    Article  CAS  Google Scholar 

  • Alconcel SN, Baas AS, Maynard HD (2011) FDA-approved poly (ethylene glycol)–protein conjugate drugs. Polym Chem 2(7):1442–1448

    Article  CAS  Google Scholar 

  • Antos JM, Chew GL, Guimaraes CP, Yoder NC, Grotenbreg GM, Popp MW, Ploegh HL (2009) Site-specific N- and C-terminal labeling of a single polypeptide using sortases of different specificity. J Am Chem Soc 131(31):10800–10801

    Article  CAS  Google Scholar 

  • Armstrong JK, Wenby RB, Meiselman HJ, Fisher TC (2003) In vivo survival of poly(ethylene glycol)-coated red blood cells in the rabbit. Blood 102:94A

    Google Scholar 

  • Armstrong JK, Hempel G, Koling S, Chan LS, Fisher T, Meiselman HJ, Garratty G (2007) Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer 110:103–111. PubMed: 17516438

    Article  Google Scholar 

  • Berg JM, Tymoczko JL, Stryer L (2002) Biochemistry, 5th edn. W H Freeman, New York. Chapter 3, Protein Structure and Function. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21177/

    Google Scholar 

  • Blaschke UK, Silberstein J, Muir TW (2000) Protein engineering by expressed protein ligation. Methods Enzymol 328:478–496

    Article  CAS  Google Scholar 

  • Borchmann DE, Carberry TP, Weck M (2014) “Bio”-macromolecules: polymer-protein conjugates as emerging scaffolds for therapeutics. Macromol Rapid Commun 35(1):27–43

    Article  CAS  Google Scholar 

  • Cheng TL, Cheng CM, Chen BM, Tsao DA, Chuang KH, Hsiao SW, Lin YH, Roffler SR (2005) Monoclonal anti-body-based quantitation of poly(ethylene glycol)-derivatized proteins, liposomes, and nanoparticles. Bioconjug Chem 16:1225–1231

    Article  CAS  Google Scholar 

  • Clancy KW, Melvin JA, McCafferty DG (2010) Sortase transpeptidases: insights into mechanism, substrate specificity, and inhibition. Biopolymers 94:385–396

    Article  CAS  Google Scholar 

  • Comfort D, Clubb RT (2004 May 1) A comparative genome analysis identifies distinct sorting pathways in gram-positive bacteria. Infect Immun 72(5):2710–22

    Article  CAS  Google Scholar 

  • Dawson PE, Kent SB (2000) Synthesis of native proteins by chemical ligation. Annu Rev Biochem 69:923–960

    Article  CAS  Google Scholar 

  • Desvaux M, Dumas E, Chafsey I, He’braud M (2006) FEMS Microbiol Lett 256:1–15

    Article  CAS  Google Scholar 

  • Dozier JK, Distefano MD (2015) Site-specific PEGylation of therapeutic proteins. Int J Mol Sci 16(10):25831–25864

    Article  CAS  Google Scholar 

  • Dramsi S, Trieu-Cuot P, Bierne H (2005) Sorting sortases: a nomenclature proposal for the various sortases of gram-positive bacteria. Res Microbiol 156(3):289–297

    Article  CAS  Google Scholar 

  • Garratty G (2004) Progress in modulating the RBC membrane to produce transfusable universal/stealth donor RBCs. Transfus Med Rev 18:245–256

    Article  Google Scholar 

  • Global Data (2015). http://www.globaldata.com. 2015

  • Gordon MR et al (2015) Field guide to challenges and opportunities in antibody drug conjugates for chemists. Bioconjug Chem 26:2198–2215

    Article  CAS  Google Scholar 

  • Graham ML (2003) Pegaspargase: a review of clinical studies. Adv Drug Deliv Rev 55:1293–1302

    Article  CAS  Google Scholar 

  • Harris JM, Chess RB (2003) Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2(3):214–221

    Article  CAS  Google Scholar 

  • Jackson DY, Burnier J, Quan C, Stanley M, Tom J et al (1994) A designed peptide ligase for total synthesis of ribonuclease A with unnatural catalytic residues. Science 266:243–247

    Article  CAS  Google Scholar 

  • Jacobitz AW, Kattke MD, Wereszczynski J, Clubb RT (2017) Sortase Transpeptidases: structural biology and catalytic mechanism. Adv Protein Chem Struct Biol 109:223–264. https://doi.org/10.1016/bs.apcsb.2017.04.008

    Article  CAS  Google Scholar 

  • Kerwin BA, Chang BS, Gegg CV, Gonnelli M, Li T, Strambini GB (2002) Interactions between PEG and type I soluble tumor necrosis factor receptor: modulation by pH and by PEGylation at the N terminus. Protein Sci 11:1825–1833

    Article  CAS  Google Scholar 

  • Kinstler O, Moulinex G, Treheit M, Ladd D, Gegg C (2002) Mono-N-terminal poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 54:477–485

    Article  CAS  Google Scholar 

  • Knop K, Hoogenboom R, Fischer D, Schubert US (2010) Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed 49:6288–6308

    Article  CAS  Google Scholar 

  • Krug LM, Ragupathi G, Ng KK, Hood C, Jennings HJ, Guo Z, Kris MG, Miller V, Pizzo B, Tyson L, Baez V, Livingston PO (2004) Clin Cancer Res 10:916–923

    Article  CAS  Google Scholar 

  • Lau GKK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW et al (2005) Peginterferon α-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis b. N Engl J Med 352:2682–2695

    Article  CAS  Google Scholar 

  • Levary DA, Parthasarathy R, Boder ET, Ackerman ME (2011) Protein-protein fusion catalyzed by sortase A. PLoS One 6(4):e18342

    Article  CAS  Google Scholar 

  • Li F, Mahato RI (2017) Bioconjugate therapeutics: current progress and future perspective. Mol Pharm 14(5):1321–1324

    Article  CAS  Google Scholar 

  • Malik NN (2008) Drug discovery: past, present and future. Drug Discov Today 13(21–22):909–912

    Article  Google Scholar 

  • Maresso AW, Schneewind O (2008) Sortase as a target of anti-infective therapy. Pharmacol Rev 60(1):128–141

    Article  CAS  Google Scholar 

  • Marraffini LA, Dedent AC, Schneewind O (2006) Microbiol Mol Biol Rev 70:192–221

    Article  CAS  Google Scholar 

  • Mazmanian SK (1999) Staphylococcus aureus Sortase, an enzyme that anchors surface proteins to the cell wall. Science 285:760–763

    Article  CAS  Google Scholar 

  • Mazmanian SK, Liu G, Jensen ER, Lenoy E, Schneewind O (2000) Staphylococcus aureus sortase mutants defective in the display of surface proteins and in the pathogenesis of animal infections. Proc Natl Acad Sci U S A 97:5510–5515

    Article  CAS  Google Scholar 

  • Mazmanian SK, Ton-That H, Schneewind O (2001) Mol Microbiol 40:1049–1057

    Article  CAS  Google Scholar 

  • McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER et al (2009) Peginterferon α-2b or α-2a with ribavirin for treatment of hepatitis c infection. N Engl J Med 361:580–593

    Article  CAS  Google Scholar 

  • Mero A, Clementi C, Veronese FM, Pasut G (2011) Covalent conjugation of poly (ethylene glycol) to proteins and peptides: strategies and methods. In: Bioconjugation protocols. Humana Press, Totowa, pp 95–129

    Chapter  Google Scholar 

  • Monfardini C, Schiavon O, Caliceti P et al (1995) A branched monomethoxypoly(ethylene glycol) for protein modification. Bioconjug Chem 6:62–69

    Article  CAS  Google Scholar 

  • Palomares LA, Kuri-Breña F, Ramírez OT (2002) Industrial recombinant protein production. In: The Encyclopedia of Life Support Systems, vol 6. EOLSS Publishers, Oxford. (3.8)

    Google Scholar 

  • Parthasarathy R, Subramanian S, Boder ET (2007) Sortase a as a novel molecular “stapler” for sequence-specific protein conjugation. Bioconjug Chem 18(2):469–476

    Article  CAS  Google Scholar 

  • Pelegri-O’Day EM, Lin E-W, Maynard HD (2014) Therapeutic protein−polymer conjugates: advancing beyond PEGylation. J Am Chem Soc 136(41):14323–14332. PubMed: 25216406

    Article  CAS  Google Scholar 

  • Pisal DS, Kosloski MP, Balu-Iyer SV (2010a) Delivery of therapeutic proteins. J Pharm Sci 99(6):2557–2575

    Article  CAS  Google Scholar 

  • Pisal DS, Kosloski MP, Balu-Iyer SV (2010b) Delivery of therapeutic proteins. J Pharm Sci 99(6):2557–2575

    Article  CAS  Google Scholar 

  • Popp MWL, Ploegh HL (2011) Making and breaking peptide bonds: protein engineering using sortase. Angew Chem Int Ed 50:5024–5032

    Article  CAS  Google Scholar 

  • Popp MW, Dougan SK, Chuang TY, Spooner E, Ploegh HL (2011) Sortase-catalyzed transformations that improve the properties of cytokines. Proc Natl Acad Sci U S A 108:3169–3174

    Article  CAS  Google Scholar 

  • QI MIDAS MAT Q2 (2016) LCUS$ used for growth figures

    Google Scholar 

  • QI MIDAS MAT Q4 (2015) ex-manufacturer level pricing, excludes discounts and rebates

    Google Scholar 

  • Richter AW, Åkerblom E (1983) Antibodies against polyethylene glycol produced in animals by immunization with monomethoxy polyethylene glycol modified proteins. Int Arch Allergy Appl Immunol 70:124–131

    Article  CAS  Google Scholar 

  • Roberts MJ, Harris JM (1998) Attachment of degradable poly(ethylene glycol) to proteins has the potential to increase therapeutic efficacy. J Pharm Sci 87(11):1440–1445

    Article  CAS  Google Scholar 

  • Sanchez-Garcia L, Martín L, Mangues R, Ferrer-Miralles N, Vázquez E, Villaverde A (2016) Recombinant pharmaceuticals from microbial cells: a 2015 update. Microb Cell Factories 15(1):33

    Article  CAS  Google Scholar 

  • Schwartz RS (2004a) Paul Ehrlich’s magic bullets. New Engl J Med 350:1079–1080

    Article  CAS  Google Scholar 

  • Schwartz RS (2004b) Paul Ehrlich’s magic bullets. N Engl J Med 350(11):1079–1080

    Article  CAS  Google Scholar 

  • Seeberger PH, Werz DB (2007) Synthesis and medical applications of oligosaccharides. Nature 446(7139):1046

    Article  CAS  Google Scholar 

  • Sherman MR, Saifer MG, Perez-Ruiz F (2008) PEG-Uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev 60:59–68

    Article  CAS  Google Scholar 

  • Shimizu T, Ichihara M, Yoshioka Y, Ishida T, Nakagawa S, Kiwada H (2012) Intravenous administration of polyethylene glycol-coated (PEGylated) proteins and PEGylated adenovirus elicits an anti-PEG immunoglobulin M response. Biol Pharm Bull 35:1336–1342

    Article  CAS  Google Scholar 

  • Singh HB, Jha A, Keswani C (eds) (2016) Intellectual property issues in biotechnology. CABI, Wallingford. 304 pages, ISBN-13: 9781780646534

    Google Scholar 

  • Singh HB, Keswani C, Singh SP (eds) (2019a) Intellectual property issues in microbiology. Springer-Nature, Singapore. 425 pages, ISBN- 9789811374654

    Google Scholar 

  • Singh HB, Keswani C, Reddy MS, Royano ES, García-Estrada C (2019b) Secondary metabolites of plant growth promoting Rhizomicroorganisms: discovery and applications. Springer-Nature, Singapore. 392 pages, ISBN- 978-981-13-5861-6

    Book  Google Scholar 

  • Sroda K, Rydlewski J, Langner M, Kozubek A, Grzybek M, Sikorski AF (2005) Repeated injections of PEG-PE liposomes generate anti- PEG antibodies. Cell Mol Biol Lett 10:37–47

    CAS  Google Scholar 

  • Sundy JS, Ganson NJ, Scarlett E, Rehrig CD, Huang W, Hershfield MS (2007) Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum 56:1021–1028. PubMed: 17328081

    Article  CAS  Google Scholar 

  • Tang L, Persky AM, Hochhaus G, Meibohm B (2004) Pharmacokinetic aspects of biotechnology products. J Pharm Sci 93(9):2184–2204

    Article  CAS  Google Scholar 

  • Tegnér F (2015) Optimization of a PEGylation process A combined reaction and separation with size exclusion reaction chromatography. Department of Chemical Engineering Lund University May 2015

    Google Scholar 

  • Ton-That H, Marraffini LA, Schneewind O (2004) Biochim Biophys Acta 1694:269–278

    Article  CAS  Google Scholar 

  • Van Vught R, Pieters RJ, Breukink E (2014) Site-specific functionalization of proteins and their applications to therapeutic antibodies. Comput Struct Biotechnol J 9(14):e201402001

    Article  Google Scholar 

  • Verez-Bencomo V, Fernandez-Santana V, Hardy E, Toledo ME, Rodríguez MC, Heynngnezz L, Rodriguez A, Baly A, Herrera L, Izquierdo M, Villar A (2004) A synthetic conjugate polysaccharide vaccine against Haemophilus influenzae type B. Science 305(5683):522–525

    Article  CAS  Google Scholar 

  • Veronese FM (2001) Peptide and protein PEGylation: a review of problems and solutions. Biomaterials 22:405–417

    Article  CAS  Google Scholar 

  • Veronese FM, Pasut G (2005) PEGylation, successful approach to drug delivery. Drug Discov Today 10:1451–1458. PubMed: 16243265

    Article  CAS  Google Scholar 

  • Veronese FM, Mero A, Caboi F, Sergi M, Marongiu C, Pasut G (2007) Bioconjug Chem 18(6):1824–1830

    Article  CAS  Google Scholar 

  • Warden-Rothman R, Caturegli I, Popik V, Tsourkas A (2013) Sortase-Tag Expressed Protein Ligation (STEPL): combining protein purification and site-specific bioconjugation into a single step. Anal Chem 85(22):11090. https://doi.org/10.1021/ac402871k

    Article  CAS  Google Scholar 

  • Witte MD, Theile CS, Wu T, Guimaraes CP, Blom AEM, Ploegh HL (2013) Production of unnaturally linked chimeric proteins using a combination of sortase-catalyzed transpeptidation and click chemistry. Nat Protoc 8:1808–1819

    Article  CAS  Google Scholar 

  • Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, Longerich T, Schirmacher P, Metzler F, Zankel M et al (2006) Peginterferon α-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis b. Hepatology 44:675–684

    Article  CAS  Google Scholar 

  • Zhang F, Liu M-r, Wana H-t (2014) Discussion about several potential drawbacks of PEGylated therapeutic proteins. Biol Pharm Bull 37(3):335–339

    Article  CAS  Google Scholar 

  • Zong Y, Bice TW, Ton-That H, Schneewind O, Narayana SV (2004) Crystal structures of Staphylococcus aureus sortase A and its substrate complex. J Biol Chem 279:31383–31389

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Health Sciences, Lahore, Pakistan

    Nasir Mahmood

  2. Department of Cell and Systems Biology, University of Toronto, Toronto, Canada

    Nasir Mahmood & Kathleen Hefferon

  3. Abdus Salam School of Sciences, Nusrat Jahan College, Rabwah, Chiniot, Pakistan

    Sarah Bushra Nasir

Authors
  1. Nasir Mahmood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah Bushra Nasir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathleen Hefferon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen Hefferon .

Editor information

Editors and Affiliations

  1. Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India

    Chetan Keswani

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mahmood, N., Nasir, S.B., Hefferon, K. (2020). Conjugated Recombinant Proteins as Emerging New Drugs. In: Keswani, C. (eds) Bioeconomy for Sustainable Development. Springer, Singapore. https://doi.org/10.1007/978-981-13-9431-7_18

Download citation

Publish with us

Policies and ethics

Search

Navigation