Designing and identifying β-hairpin peptide macrocycles with antibiotic potential.

Autor:	Randall JR; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., DuPai CD; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.; Department of Integrative Biology, University of Texas at Austin, Austin, TX, USA., Cole TJ; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.; Department of Integrative Biology, University of Texas at Austin, Austin, TX, USA., Davidson G; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., Groover KE; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., Slater SL; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., Mavridou DAI; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., Wilke CO; Department of Integrative Biology, University of Texas at Austin, Austin, TX, USA., Davies BW; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2023 Jan 13; Vol. 9 (2), pp. eade0008. Date of Electronic Publication: 2023 Jan 11.
DOI:	10.1126/sciadv.ade0008
Abstrakt:	Peptide macrocycles are a rapidly emerging class of therapeutic, yet the design of their structure and activity remains challenging. This is especially true for those with β-hairpin structure due to weak folding properties and a propensity for aggregation. Here, we use proteomic analysis and common antimicrobial features to design a large peptide library with macrocyclic β-hairpin structure. Using an activity-driven high-throughput screen, we identify dozens of peptides killing bacteria through selective membrane disruption and analyze their biochemical features via machine learning. Active peptides contain a unique constrained structure and are highly enriched for cationic charge with arginine in their turn region. Our results provide a synthetic strategy for structured macrocyclic peptide design and discovery while also elucidating characteristics important for β-hairpin antimicrobial peptide activity.
Databáze:	MEDLINE
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