De novo design of mini-proteins as specific binders to PACAP-38, a key mediator of migraine

De novo designed miniprotein ICLIST-11 binds PACAP-38 with KD = 4.51 nM and neutralizes PACAP-38–induced PAC1R activation with IC50 = 10.6 nM.

• Why it matters: PACAP-38 is a key vasoactive mediator linked to migraine, and current antibody approaches motivate medium-molecular-weight binders that can act as ligand traps.
• What they did: Using Bindcraft, binders were designed and ICLIST-2 (63 residues) was found with KD = 26.5 nM; alanine scanning and structural analysis then guided ProteinMPNN to create ICLIST-11 with nine substitutions.
• The result: Structural modeling and MD simulations implicated E30F, M31L, and R54W in improved stability (Tm +14 °C) and affinity, enabling stronger, concentration-dependent neutralization versus ICLIST-2 in cell assays.

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