Replacement of a peptide bond with a peptide bond isostere is an established approach for enhancing metabolic stability, potency, and selectivity. Among these, fluoroalkene dipeptide isosteres (FADIs) have been widely studied as near-ideal mimics of peptide bond geometry and electronics. In contrast, chloroalkene dipeptide isosteres (CADIs), despite possessing a chlorine atom that serves as a carbonyl oxygen equivalent with unique steric and stereoelectronic properties, have long been overlooked.
In our ongoing efforts to develop new peptidomimetics, we have established multi-gram scale and diastereoselective synthetic strategies for (Z)-CADIs.[1] In this presentation, we will introduce the synthesis of various CADI-containing peptidomimetics and highlight their broad applications beyond β-turn mimics, including G4-binding peptides,[2] hNMUR agonists,[3] and other bioactive sequences. We will also discuss recent findings showing that CADI substitution enhances membrane permeability due to its increased hydrophobicity.[4]
Furthermore, we have expanded the utility of ADIs to improve the enzymatic stability of protein-based constructs. By replacing the Gly75–Gly76 peptide bond of ubiquitin with alkene-type isosteres, we created Ub mimics that resist cleavage by deubiquitinases while retaining the native isopeptide linkage targeted for hydrolysis.5 This approach effectively prevents enzyme recognition at the modified peptide bond and offers a general strategy to stabilize ubiquitin conjugates and related proteins.
Together, these studies reposition CADIs from an overlooked isostere to an essential multifunctional tool in modern peptidomimetic and protein design.