Backbone Alterations in Cyclic Peptides Influence Both Membrane Permeability and Biological Activity

Cyclic peptides hold significant potential as disruptors
of challenging
targets such as protein–protein interactions, but their poor
passive membrane permeability limits their use. In this study, we
used a combination of cell-permeability assays and a target-agnostic
cell-painting assay to observe how minimal structural changes affect
membrane permeability and the biological activity of Sanguinamide
A analogues. Significant differences in permeability were observed
among the analogues, and for those that were permeable, NMR spectroscopy
revealed conformational changes in response to environmental polarity.
In the cell-painting assay, we observed that even though permeability
generally correlated with overall morphological changes, distinct
differences in specific activities were observed depending on the
nature of the backbone modification. These findings highlight the
importance of selecting the correct backbone modification when trying
to balance both membrane permeability and biological activity, offering
valuable insights for the development of cyclic peptides as therapeutic
agents.