Stereorandomization as a Method to Probe Peptide Bioactivity

Siriwardena, Thissa N.; Gan, Bee-Ha; Köhler, Thilo; van Delden, Christian; Javor, Sacha; Reymond, Jean-Louis (2021). Stereorandomization as a Method to Probe Peptide Bioactivity. ACS central science, 7(1), pp. 126-134. ACS Publications 10.1021/acscentsci.0c01135

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Solid-phase peptide synthesis (SPPS) is usually performed with optically pure building blocks to prepare peptides as single enantiomers. Herein we report that SPPS using racemic amino acids provides stereorandomized (sr) peptides, containing up to billions of different stereoisomers, as well-defined single HPLC peaks, single mass products with high yield, which can be used to investigate peptide bioactivity. To exemplify our method, we show that stereorandomization abolishes the membrane-disruptive effect of α-helical amphiphilic antimicrobial peptides but preserves their antibiofilm effect, implying different mechanisms involving folded versus disordered conformations. For antimicrobial peptide dendrimers by contrast, stereorandomization preserves antibacterial, membrane-disruptive, and antibiofilm effects but reduces hemolysis and cytotoxicity, thereby increasing their therapeutic index. Finally, we identify partially stereorandomized analogues of the last resort cyclic peptide antibiotic polymyxin B with preserved antibacterial activity but lacking membrane-disruptive and lipopolysaccharide-neutralizing activity, pointing to the existence of additional targets.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Siriwardena, Thissa Appuhamilage; Gan, Bee Ha; Javor, Sacha and Reymond, Jean-Louis

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

2374-7943

Publisher:

ACS Publications

Language:

English

Submitter:

Sandra Tanja Zbinden Di Biase

Date Deposited:

19 Jan 2022 14:30

Last Modified:

05 Dec 2022 15:59

Publisher DOI:

10.1021/acscentsci.0c01135

PubMed ID:

33532575

BORIS DOI:

10.48350/162976

URI:

https://boris.unibe.ch/id/eprint/162976

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