Fig. 3: Membrane permeability correlates with peptide lipophilicity, but acidic residues can be accommodated at select positions.
From: Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
a The ATSP-7041 core sequence is amphipathic as demonstrated by a helical wheel depiction where residues are coloured according to polarity; residues in black are apolar, those in blue are acidic, and those in green are uncharged polar. Application of a full glutamic acid scan of this amphipathic sequence demonstrates that placement of a Glu residue on the apolar helical face tended to decrease NanoClick permeability whereas placement on the polar face was generally tolerated. b Library analysis reveals that permeability (cell ratio = cellular EC50 / binding KD) is correlated with lipophilicity (LogD). To avoid the confounding effects of polypharmacology, peptides included were restricted to those that had a Mdm2 KD value < 10uM and had cell activities that were at least 10x greater than the potencies in the counterscreen and LDH assays.
