Rational design of α-helix-stabilized exendin-4 analogues

Petra Rovó, Viktor Farkas, Pál Stráner, Mária Szabó, Ágnes Jermendy, Orsolya Hegyi, G. Tóth, A. Perczel

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Exendin-4 (Ex4) is a potent glucagon-like peptide-1 receptor agonist, a drug regulating the plasma glucose level of patients suffering from type 2 diabetes. The molecule's poor solubility and its readiness to form aggregates increase the likelihood of unwanted side effects. Therefore, we designed Ex4 analogues with improved structural characteristics and better water solubility. Rational design was started from the parent 20-amino acid, well-folded Trp cage (TC) miniprotein and involved the step-by-step N-terminal elongation of the TC head, resulting in the 39-amino acid Ex4 analogue, E19. Helical propensity coupled to tertiary structure compactness was monitored and quantitatively analyzed by electronic circular dichroism and nuclear magnetic resonance (NMR) spectroscopy for the 14 peptides of different lengths. Both 15N relaxation- and diffusion-ordered NMR measurements were established to investigate the inherent mobility and self-association propensity of Ex4 and E19. Our designed E19 molecule has the same tertiary structure as Ex4 but is more helical than Ex4 under all studied conditions; it is less prone to oligomerization and has preserved biological activity. These conditions make E19 a perfect lead compound for further drug discovery. We believe that this structural study improves our understanding of the relationship between local molecular features and global physicochemical properties such as water solubility and could help in the development of more potent Ex4 analogues with improved pharmacokinetic properties.

Original languageEnglish
Pages (from-to)3540-3552
Number of pages13
JournalBiochemistry
Volume53
Issue number22
DOIs
Publication statusPublished - Jun 10 2014

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Solubility
Magnetic Resonance Spectroscopy
Magnetic resonance measurement
Lead compounds
Amino Acids
Oligomerization
Molecules
Pharmacokinetics
Water
Drug Discovery
Medical problems
Circular Dichroism
Bioactivity
exenatide
Type 2 Diabetes Mellitus
Nuclear magnetic resonance spectroscopy
Elongation
Head
Nuclear magnetic resonance
Association reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Rovó, P., Farkas, V., Stráner, P., Szabó, M., Jermendy, Á., Hegyi, O., ... Perczel, A. (2014). Rational design of α-helix-stabilized exendin-4 analogues. Biochemistry, 53(22), 3540-3552. https://doi.org/10.1021/bi500033c

Rational design of α-helix-stabilized exendin-4 analogues. / Rovó, Petra; Farkas, Viktor; Stráner, Pál; Szabó, Mária; Jermendy, Ágnes; Hegyi, Orsolya; Tóth, G.; Perczel, A.

In: Biochemistry, Vol. 53, No. 22, 10.06.2014, p. 3540-3552.

Research output: Contribution to journalArticle

Rovó, P, Farkas, V, Stráner, P, Szabó, M, Jermendy, Á, Hegyi, O, Tóth, G & Perczel, A 2014, 'Rational design of α-helix-stabilized exendin-4 analogues', Biochemistry, vol. 53, no. 22, pp. 3540-3552. https://doi.org/10.1021/bi500033c
Rovó P, Farkas V, Stráner P, Szabó M, Jermendy Á, Hegyi O et al. Rational design of α-helix-stabilized exendin-4 analogues. Biochemistry. 2014 Jun 10;53(22):3540-3552. https://doi.org/10.1021/bi500033c
Rovó, Petra ; Farkas, Viktor ; Stráner, Pál ; Szabó, Mária ; Jermendy, Ágnes ; Hegyi, Orsolya ; Tóth, G. ; Perczel, A. / Rational design of α-helix-stabilized exendin-4 analogues. In: Biochemistry. 2014 ; Vol. 53, No. 22. pp. 3540-3552.
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