Peptidomimetic caspase-2 inhibitors block toxic tau cleavage but face permeability and stability hurdles
- A 48-member peptidomimetic aldehyde library was built around P2/P3 modifications, and two leads reached low-nanomolar caspase-2 potency with strong selectivity against caspase-3 and other family members.
- The compounds suppressed tau cleavage and formation of the toxic Δtau314 fragment; co-crystal structures rationalized the SAR.
- A reference compound showed good ADME/PK, yet poor permeability, limited brain exposure and an unstable P5 indoline block progression.
💡 Points Based on the abstract
An aldehyde warhead on a peptidic scaffold with a labile indoline at P5 is a hard sell for CNS work, and the paper more or less concedes it. Aldehydes hydrate, epimerize and clear fast. Next step: replace the P5 block with a more robust cap, test a less promiscuous reversible warhead such as a nitrile, and check unbound brain exposure before trusting any tau readout.