Receptor-based antidote for diphtheria

Jeong Heon Cha, Joanna S. Brooke, Mee Young Chang, Leon Eidels

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Although equine diphtheria antitoxin may be an effective therapy for human diphtheria, its use often induces serum sickness. We describe here a strategy for developing an alternative treatment based on the human diphtheria toxin (DT) receptor/heparin-binding epidermal growth factor-like growth factor (HB-EGF) precursor. Recombinant mature human HB-EGF acts as a soluble receptor analog, binding radioiodinated DT and preventing its binding to the cellular DT receptor/HB-EGF precursor. However, the possibility existed that radioiodinated DT-HB-EGF complexes associate with cells due to the binding of the heparin-binding domain of recombinant HB-EGF to cell surface heparan sulfate proteoglycans. This possibility was confirmed by performing DT binding studies in the presence of heparin. A recombinant truncated HB-EGF (residues 106 to 149), which lacks most of the heparin-binding domain, showed an essentially heparin-independent binding of radioiodinated DT to cells. Furthermore, it was a more effective inhibitor of DT binding than was recombinant mature HB-EGF. Since mature HB-EGF is a known ligand for the EGF receptor and is thus highly mitogenic (tumorigenic), we then changed amino acid residues in the EGF-like domain of the recombinant truncated HB-EGF and demonstrated that this DT receptor analog (I117A/L148A) displayed a low mitogenic effect. The truncated (I117A/L148A) HB-EGF protein retained high DT binding affinity, as confirmed by using surface plasmon resonance. Our results suggest that the truncated (I117A/L148A) HB-EGF protein could be an effective, safe antidote for human diphtheria.

Original languageEnglish
Pages (from-to)2344-2350
Number of pages7
JournalInfection and Immunity
Volume70
Issue number5
DOIs
Publication statusPublished - 2002 Apr 29

Fingerprint

Antidotes
Diphtheria
Heparin
Epidermal Growth Factor
Intercellular Signaling Peptides and Proteins
Diphtheria Toxin
Diphtheria Antitoxin
Serum Sickness
Heparan Sulfate Proteoglycans
Surface Plasmon Resonance

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Cha, Jeong Heon ; Brooke, Joanna S. ; Chang, Mee Young ; Eidels, Leon. / Receptor-based antidote for diphtheria. In: Infection and Immunity. 2002 ; Vol. 70, No. 5. pp. 2344-2350.
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Cha, JH, Brooke, JS, Chang, MY & Eidels, L 2002, 'Receptor-based antidote for diphtheria', Infection and Immunity, vol. 70, no. 5, pp. 2344-2350. https://doi.org/10.1128/IAI.70.5.2344-2350.2002

Receptor-based antidote for diphtheria. / Cha, Jeong Heon; Brooke, Joanna S.; Chang, Mee Young; Eidels, Leon.

In: Infection and Immunity, Vol. 70, No. 5, 29.04.2002, p. 2344-2350.

Research output: Contribution to journalArticle

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