LAUSR

We synthesized and experimentally tested the passive permeability of more than thirty tetrapeptides mimicking the N‐terminus of the pro‐apoptotic protein Smac (Second mitochondria‐derived activator of caspases). Each peptide bore one or two unnatural Hydrogen Bond Acceptor‐bearing Amino Acid (HBA‐AA) residues, such that intramolecular hydrogen bonding with proximal backbone amide N−H donors is feasible. Passive permeability of the synthetic peptides was determined using the parallel artificial membrane permeability assay (PAMPA). Experimental permeability values were found to span three orders of magnitude, providing useful empirical guidance for the design of more permeable Smac mimetics specifically, and peptidic ligands generally.