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Three different mechanisms (gene expression, angiogenesis, cell migration) engaging three complementary biological pathways

In more severe damage, PARPs can completely deplete the cellular NAD+ pool and the cell dies (paradoxically, from lack of energy)

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The critical design decisions included: GIP backbone selection : Starting from GIP rather than GLP-1, as GIP naturally has weak cross-reactivity with GLP-1R, providing a scaffold for optimization Aib2 substitution : Replacing Ala2 with alpha-aminoisobutyric acid for DPP-4 resistance (identical strategy to semaglutide) C-terminal extension : Adding a GGPSSGAPPPS (Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser) 11-residue C-terminal extension that enhances GLP-1R binding C-20 fatty diacid acylation : Attaching an eicosanedioic acid (C-20 diacid) at Lys20 via a Glu-2xOEG linker for albumin binding The resulting molecule exhibits approximately 5:1 selectivity for GIPR over GLP-1R it is a full GIPR agonist and a partial GLP-1R agonist, yet clinically achieves superior outcomes to selective full GLP-1R agonists [7]

[DOI] [PubMed] [Google Scholar] 27.Veljaca M, Lesch CA, Pllana R, Sanchez B, Chan K, Guglietta A