Stereorandomized Oncocins with Preserved Ribosome Binding andAntibacterial Activity

Check out our latest paper Stereorandomized Oncocins with Preserved Ribosome Binding andAntibacterial Activity in Journal of Medicinal Chemistry!

Abstract

We recently showed that solid-phase peptidesynthesis using racemic amino acids yields stereorandomizedpeptides comprising all possible diastereomers as homogeneous,single-mass products that can be purified by HPLC and thatstereorandomization modulates activity, toxicity, and stability ofmembrane-disruptive cyclic and linear antimicrobial peptides(AMPs) and dendrimers. Here, we tested if stereorandomizationmight be compatible with target binding peptides with the exampleof the proline-rich AMP oncocin, which inhibits the bacterialribosome. Stereorandomization of up to nine C-terminal residuespreserved ribosome binding and antibacterial effects includingactivities against drug-resistant bacteria and protected againstserum degradation. Surprisingly, fully stereorandomized oncocin was as active as L-oncocin in dilute growth media stimulatingpeptide uptake, although it did not bind the ribosome, indicative of an alternative mechanism of action. These experiments show thatstereorandomization can be compatible with target binding peptides and can help understand their mechanism of action.

Author(s) Bee Ha Gan, Etienne Bonvin, Thierry Paschoud, Hippolyte Personne, Jérémie Reusser, Xingguang Cai, Robert Rauscher, Thilo Köhler, Christian van Delden, Norbert Polacek, and Jean-Louis Reymond