2. Academic Validation
  3. Structure-Guided Semisynthesis of Blasticidin S-Amicetin Chimeras as Selective Ribosome Inhibitors

Structure-Guided Semisynthesis of Blasticidin S-Amicetin Chimeras as Selective Ribosome Inhibitors

  • J Am Chem Soc. 2026 Jan 28;148(3):2963-2971. doi: 10.1021/jacs.5c13979.
Cole Gannett 1 2 3,  Kateland Tiller 2 3 4,  Somaia Abdelmegeed 4,  Micah Hoernig 3 5,  Ahmed A Abouelkhair 2 6,  Mohamed N Seleem 2 3 4 6,  James Weger-Lucarelli 2 3 4 6,  Anne M Brown 2 3 5 7,  Andrew N Lowell 1 2 3 8
Affiliations

Affiliations

  • 1 Department of Chemistry, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.
  • 2 Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Tech, Blacksburg, Virginia 24061, United States.
  • 3 Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.
  • 4 Department of Biomedical Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, Virginia 24061, United States.
  • 5 Department of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States.
  • 6 Center for One Health Research, Virginia Tech, Blacksburg, Virginia 24061, United States.
  • 7 Research and Informatics, University Libraries, Virginia Tech, Blacksburg, Virginia 24061, United States.
  • 8 Faculty of Health Sciences, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.
PMID: 41525473 DOI: 10.1021/jacs.5c13979
Abstract

Peptidyl nucleosides are broad-acting inhibitors, but their dense functionality and complex reactivity have historically limited the modification of these scaffolds. Guided by structural overlays and molecular modeling, we designed blasticidin S-amicetin chimeras to exploit a bacterial-specific pocket of the ribosomal PTC while reducing eukaryotic ribosome engagement. To test this hypothesis, we developed a semisynthetic route enabling sequential C6' derivatization and C4 amine coupling on the blasticidin S scaffold, facilitated by counterion exchange to prevent side reactions. This approach furnished four C6' classes (acid, methyl ester, primary amide, phenethyl amide), each diversified at C4 with para-aminobenzoate motifs, delivering densely functionalized chimeras in as few as four steps and up to 38% yield. Across the series, Antibacterial potency was retained while mammalian cytotoxicity dropped sharply, with selectivity indices approaching >50 and cytotoxicity values >256 μg/mL for the phenethyl amide series. Comparison of resolved ribosome structures supplemented by modeling rationalizes the observed selectivity gains as engagement of a termination-compatible Bacterial pocket that is disfavored during eukaryotic elongation. These results demonstrate how structure-guided semisynthesis can transform a challenging natural product into selective translation inhibitors and establish a practical framework for diversifying chemically complex scaffolds.

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