Research Projects

A macrocyclic framework is achieved by altering the chemical reactivity of the peptide bond, which should be coupled with a heavily desolvated microenvironment. Traditional methods for peptide bond desolvation involve N-methylation, but this has limitations, such as the reduction in rotational barrier and the co-existence of a cis and trans conformer. To address this, alternative methods for peptide bond desolvation are proposed. The study aims to mask Hydrogen Bond Acceptor (HBA) and Hydrogen Bond Donor (HBD) by thioamidation and N-methylation to enhance passive permeability and metabolic stability of macrocyclic peptides. The model macrocyclic peptide is cyclo(-D-Leu1-Leu-D-Pro-D-Leu-Leu-D-Ala-Pro-Leu8-) (1), which is highly permeable across the plasma membrane but shows low permeability compared to smaller cyclic hexa- and cyclic heptapeptides. The researchers plan to convert negative and positively charged patches into hydrophobic patches and assess the effect on structural alteration and net permeability across artificial and biological membranes.