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Development of Akt-activated GSK3β inhibitory peptide

Jin-Sik Kim1, Shunfu Piao, Eunjin Lee

  • 1Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.

Biochemical and Biophysical Research Communications
|April 16, 2013
PubMed

Insights

Researchers developed a novel peptide that inhibits glycogen synthase kinase 3 beta (GSK3β) only when activated by Akt. This targeted approach offers a new strategy for treating insulin resistance and type 2 diabetes mellitus.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Abnormal glycogen synthase kinase 3 beta (GSK3β) activity is linked to insulin resistance.
  • Existing GSK3β inhibitors cause side effects due to unregulated inhibition of normal GSK3β function.
  • Phosphorylation of PPPSPxS motifs in LRP6 regulates GSK3β inhibition.

Purpose of the Study:

  • To create a novel GSK3β inhibitory peptide activated by Akt.
  • To develop a regulated GSK3β inhibitor for potential therapeutic applications in insulin resistance and type 2 diabetes mellitus.

Main Methods:

  • Designed a peptide combining the PPPSPxS motif with an Akt target sequence.
  • Tested the peptide's inhibitory activity on GSK3β in purified systems.
  • Evaluated the peptide's function in cells stimulated by insulin.

Main Results:

  • The novel peptide demonstrated GSK3β inhibitory activity exclusively upon phosphorylation by Akt.
  • Insulin stimulation in cells led to Akt-mediated phosphorylation and subsequent GSK3β inhibition by the peptide.
  • The peptide's activity was regulated, showing inhibition only under specific conditions.

Conclusions:

  • A novel, Akt-activated GSK3β inhibitory peptide was successfully generated.
  • This peptide offers a regulated approach to inhibiting GSK3β, distinct from conventional inhibitors.
  • The findings present a new therapeutic concept for diseases associated with abnormal GSK3β activity, such as type 2 diabetes mellitus.

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