Membrane Permeability in Cyclic Peptides is Modulated by Core Conformations

Flaviu Cipcigan*, Paul Smith, Jason Crain, Anders Hogner, Leonardo De Maria, Antonio Llinas, Ekaterina Ratkova

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Cyclic peptides have the potential to bind to challenging targets, which are undruggable with small molecules, but their application is limited by low membrane permeability. Here, using a series of cyclic pentapeptides, we showed that established physicochemical criteria of permeable peptides are heavily violated. We revealed that a dominant core conformation, stabilized by amides' shielding pattern, could guide the design of novel compounds. As a result, counter-intuitive strategies, such as incorporation of polar residues, can be beneficial for permeability. We further find that core globularity is a promising descriptor, which can extend the capability of standard predictive models.

Original languageEnglish
Pages (from-to)263-269
Number of pages7
JournalJOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume61
Issue number1
DOIs
Publication statusPublished - 25 Jan 2021

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