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Designing GLP-1R peptide agonists in multi-objective optimisation

#Rational Peptide Design #Multi-Objective Optimisation #HomologyModelling #GPCRs #Type 2 Diabetes

Context

As part of an academic–industry collaboration on peptide therapeutics, I co-led a study to engineer improved analogues of glucagon-like peptide-1 (GLP-1), a key incretin hormone in the treatment of type 2 diabetes and obesity.


Client/Partner Type

Academic–Industry Collaboration (UQ, Pfizer)


Challenge

GLP-1 analogues can stimulate both cAMP production and β-arrestin 2 signalling. The goal was to optimise sequence and structure to enhance insulin secretion and receptor activation.


Solution

  • Designed and tested over a dozen GLP-1 peptide analogues with helical constraints and non-canonical amino acid substitutions

  • Integrated structural modelling and SAR interpretation to guide analogue selection

  • Focused on tuning helical propensity, proteolytic stability, and functional bias

  • Worked across synthesis, pharmacology, and in silico analysis teams to coordinate evaluation of binding and signalling outcomes


Outcome

  • Identified GLP-1 analogues with up to 5-fold increased cAMP activity and enhanced insulin secretion in cell models

  • Achieved minimal β-arrestin 2 recruitment, creating candidates with reduced risk of receptor desensitisation

  • Published in Eur. J. Med. Chem. (2017) and contributed to the broader understanding of biased agonism in peptide drug design


    Plisson, F.#; Hill, T. A.#; Mitchell, J. M.; Hoang, H. N.; de Araujo, A. D.; Xu, W. J.; Cotterell, A.; Edmonds, D. J.; Stanton, R. V.; Derksen, D. R.; Loria, P. M.; Griffith, D. A.; Price, D. A.; Liras, S. & Fairlie, D. P.*. Helix-constraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not β-arrestin 2 signalling European Journal of Medicinal Chemistry 2017, 127, 703-714. [DOI]


Tools/Expertise Used

Peptide modeling (PyMOL, in-house tools), structure–activity analysis, functional assays (cAMP, β-arrestin, helical propensity, insulin secretion), helix-stapling chemistry


N.B. This work now underpins Ingenie Bio’s multi-objective peptide optimisation services for metabolic and GPCR-targeted therapies.

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