Structure-based design and synthesis of group A streptogramins that bind to the nascent peptide exit tunnel of the ribosome

2026-05-09

PRE

Isabel J. Lee

Qi Li *

Tushar Raskar

J. Pellegrino

Andrew K. Ecker

Sara Y. Howard

James S. Fraser

Ian B. Seiple *

DOI：10.1016/j.ejmech.2026.118947

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Abstract

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• Designed novel C4-modified group A streptogramins to increase binding contacts in the ribosome. • Cryo-EM of 38d and 48a reveal new π-stacking interactions with U1782-U2568. • Analogs 38 had favorable binding and in vitro inhibitory activity, but poor cellular activity. • Used TPSA to design alkyl linker analogs with improved cellular permeability. • Analogs 48 and 55 showed enhanced activity against multiple strains compared to 38 and VM2.

Keywords:

streptogramins

ribosome binding

cryo-EM

π-stacking interactions

cellular permeability

Structure-based design and synthesis of group A streptogramins that bind to the nascent peptide exit tunnel of the ribosome

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