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.