Next-Generation GLUT Inhibitors: Lactone to Lactam Conversion in Rapaglutin A Confers Resistance to Plasma Esterases.

Rapaglutin A (RgA) is a potent pan-class I glucose transporter (GLUT) inhibitor identified from the rapafucin library. However, its development is hindered by plasma instability due to the rapid hydrolysis of lactone moieties by carboxylesterases, especially in rodents. To improve its stability, we designed and synthesized RgA analogues in which the lactones were substituted with more stable lactams. We found that substitution of either lactone-enhanced plasma stability, while dual lactam replacement produced the greatest improvement in mouse plasma, which has a high esterase activity. Importantly, the lactam analogues retained most of the inhibitory activity of the parent RgA against GLUT in DLD1 cells. This approach offers a promising strategy to enhance the plasma stability of RgA without significantly compromising its activity, with potential applicability across the rapafucin class of macrocycles.

• Publication year

  2025

• Venue

  ACS Medicinal Chemistry Letters

• Publication date

  2025-10-09

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acsmedchemlett.5c00470PMID 41257007PMCID PMC12621015
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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