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]
Todos analizaron el compuesto de 3 episodios adversos cardiovasculares mayores (MACE), que inclua muerte cardiovascular, infarto de miocardio no mortal o ictus no mortal, excepto el estudio con lixisenatida que consider el MACE de 4 puntos, que inclua adems hospitalizacin por insuficiencia cardaca (tabla 1)5764
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Duo H, Akhilesh S, Grace M B, Chris M F, Antony J K, Richard B G
Conserved RNA polymerase II initiation complex structure
Rhrich M, Koelsche C, Schrimpf D et al
