Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors

Direct chemical modifications provide a simple and effective means to "translate" bioactive helical peptides into potential therapeutics targeting intracellular protein-protein interactions. We previously showed that distance-matching bisaryl cross-linkers can reinforce peptide helices containing two cysteines at the i and i+7 positions and confer cell permeability to the cross-linked peptides. Here we report the first crystal structure of a biphenyl-cross-linked Noxa peptide in complex with its target Mcl-1 at 2.0 a resolution. Guided by this structure, we remodeled the surface of this cross-linked peptide through side-chain substitution and N-methylation and obtained a pair of cross-linked peptides with substantially increased helicity, cell permeability, proteolytic stability, and cell-killing activity in Mcl-1-overexpressing U937 cells

Design of Potent and Proteolytically Stable Oxyntomodulin Analogs

Incretin-based peptides are effective therapeutics for treating type 2 diabetes mellitus (T2DM). Oxyntomodulin (OXM), a dual agonist of GLP-1R and GCGR, has shown superior weight loss and glucose lowering effects, compared to single GLP-1R agonists. To overcome the short half-life and rapid renal clearance of OXM, which limit its therapeutic potential, both lipid and PEG modified OXM analogs have been reported. However, these approaches often result in reduced potency or PEG-associated toxicity. Herein, we report a new class of cross-linked OXM analogs that show increased plasma stability and higher potency in activating both GLP-1R and GCGR. Moreover, the extended <i>in vivo</i> half-life results in superior antihyperglycemic activity in mice compared to the wild-type OXM