GLP-Tweaks: stabilized GLP-1 analogues via NCAA backbone substitution

About

GLP-1 analogues lose potency to DPP-4 cleavage at the N-terminal His-Ala bond. We're testing whether NCAA substitution at position 2 gives a better serum-half-life-to-binding-penalty trade-off than the standard lipid-conjugation route. Pre-registered milestones, third-party assay vendor, all attestations signed.

Researcher

Milestones

1. 01Synthesize 6-analogue NCAA panel

   Synthesize and HPLC-purify six GLP-1 analogues with NCAA substitution at position 2, ≥95% purity.

   Pending

   Deadline: in 21dTranche: $1.2KOutputs:Synthesis reportHPLC tracesMass spec

2. 02Plasma-stability assay (DPP-4 + serum)

   Quantify half-life vs native GLP-1 across both DPP-4 and pooled human serum, n=3.

   Pending

   Deadline: in 8wTranche: $1.2KOutputs:Stability datasetAssay protocol

3. 03In-vitro receptor binding (GLP-1R)

   Measure receptor binding affinity for all six analogues; report Ki vs native.

   Pending

   Deadline: in 13wTranche: $1.2KOutputs:Binding datasetLab report

4. 04Mouse PK pilot for top analogue

   Single-dose PK study (n=4) for the best stability/binding analogue.

   Pending

   Deadline: in 21wTranche: $2.0KOutputs:PK datasetCRO reportPreprint draft

Connected sources

• GitHub

  amelia-eth/glp-tweaks

  watching since 6d ago

• arXiv

  Amelia W. (bioRxiv)

  watching since 6d ago

Anchor literature

• GLP-1 physiology, pharmacology, and clinical applications of incretin therapiesD. J. Drucker · Cell Metabolism · 2022Reference review of GLP-1 receptor agonists — mechanism, half-life engineering via lipid conjugation and stapling, clinical landscape.
• Mechanisms of action and therapeutic application of GLP-1D. J. Drucker · Nature Reviews Endocrinology · 2018Earlier mechanism-focused review used as the introductory scaffold for most GLP-1 analogue design papers.

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