An interactive reference mapping the chemical architecture, unnatural residue modifications, receptor signaling cascades, and clinical pharmacology of therapeutic peptides.
Aib⁸) and fatty diacid lipidation turn transient hormones into once-weekly therapeutics.
Unmodified native peptides are cleared by renal filtration and cleaved by endogenous peptidases (DPP-4, NEP) within minutes. Four rational design strategies transform unstable sequences into precision drugs.
Replacing standard L-residues at enzymatic cleavage sites with sterically hindered blocks like Aib (α-aminoisobutyric acid) or D-amino acids prevents DPP-4 and trypsin recognition without disrupting receptor affinity.
His⁷–[Aib⁸]–Glu⁹–Gly¹⁰
Semaglutide / Tirzepatide Position-8 Shield
Conjugating a C18 or C20 fatty diacid chain via a hydrophilic γGlu-2×OEG spacer onto a lysine side chain enables non-covalent binding to human serum albumin (HSA), shielding the peptide from glomerular filtration.
Lys²⁶–γGlu–OEG₂–C18 Diacid
>99% Plasma Albumin Bound in Circulation
All-hydrocarbon crosslinks (via ring-closing olefin metathesis at i, i+4 or i, i+7 positions) lock linear peptides into rigid α-helices capable of penetrating cell membranes and disrupting intracellular PPIs like p53–MDM2.
cyclo[i, i+4] RCM Olefin Staple
Restores α-Helicity & Cell Permeability
Homing motifs like cyclic RGD (integrin αvβ3) or somatostatin analogs (Octreotide/Dotatate) deliver cytotoxic warheads or β-emitting radioisotopes (¹⁷⁷Lu) directly into tumor cells with rapid systemic clearance.
Homing Peptide – Cleavable Linker – Payload
Lutathera (¹⁷⁷Lu-Dotatate) · PDC Architecture
Logarithmic comparison illustrating how chemical modifications extend circulation from 2 minutes to 7+ days.
Interactive pathway diagram comparing downstream intracellular cascades across Class B1 G-protein-coupled receptors.
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