Rapamycin-inspired macrocycles with new target specificity.

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Pharmacology

Background:

• Rapamycin and FK506 are natural products that bind FKBP (FK506-binding protein) before targeting mTOR (mechanistic target of rapamycin) and calcineurin, respectively.
• This dual-binding mechanism inspired the development of new molecular probes.
• Targeting new cellular proteins beyond mTOR and calcineurin is a key goal in drug discovery.

Purpose of the Study:

• To create a rapamycin-like macromolecule library targeting novel cellular proteins.
• To develop a robust macrocyclization method for synthesizing diverse hybrid macrocycles.
• To identify new chemical probes and drug leads using this library.

Main Methods:

• Developed a macrocyclization strategy using ring-closing metathesis.
• Synthesized a library of 45,000 hybrid macrocycles (rapafucins) with optimized FKBP-binding domains.
• Screened the rapafucin library in human cells to identify inhibitors of cellular processes.

Main Results:

• Discovered rapadocin, a potent, isoform-specific, and FKBP-dependent inhibitor of nucleoside uptake.
• Rapadocin specifically targets the equilibrative nucleoside transporter 1 (ENT1).
• Rapadocin demonstrated efficacy in an animal model of kidney ischemia reperfusion injury.

Conclusions:

• Rapafucins represent a new class of chemical probes and potential drug leads.
• This approach successfully expands the range of druggable protein targets.
• Rapadocin shows therapeutic potential for kidney injury and highlights the utility of rapafucins for discovering inhibitors of nucleoside transporters.