First synthetic PAPP-A inhibitors dampen IGF-1 signaling in cells and in vivo
- PAPP-A is a secreted metalloproteinase that cleaves IGF-binding proteins to control local IGF signaling, offering an alternative to IGF-1R targeting.
- Inhibitors were built on an IGFBP-5-derived anchor sequence, with the scissile bond replaced by phosphinate or phosphonate groups, giving potent and selective compounds.
- Cryo-EM showed how they bind the active site, and they blocked IGFBP-4 and IGFBP-5 cleavage.
- They suppressed IGF-1 signaling in A549 cells, comparably to stanniocalcin-1, and inhibited Papp-aa-dependent signaling in vivo.
💡 Points
Swapping the scissile bond of an IGFBP-5 anchor sequence for a phosphinate or phosphonate is classic transition-state mimicry, and a cryo-EM pose would validate the zinc-binding hypothesis. Going after the protease rather than IGF-1R is smart for selectivity. I'd want Ki values against related metalloproteinases, and cell permeability and stability of these peptidic leads, before trusting the in vivo claim.