Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Microbiology

Background:

• FK506-binding proteins (FKBPs) are conserved enzymes with peptidyl-prolyl isomerase activity, crucial for various cellular processes and acting as targets for immunosuppressants.
• Microbial macrophage-infectivity-potentiator (Mip)-type FKBPs are implicated in enhancing pathogen infectivity.
• Developing effective, druglike ligands for FKBPs and Mips remains a significant challenge in drug discovery.

Purpose of the Study:

• To explore the potential of C5-substituted [4.3.1]-aza-bicyclic sulfonamides as a versatile class of FKBP and Mip inhibitors.
• To develop a novel synthesis for the bicyclic core scaffold to facilitate library generation.
• To conduct a structure-activity relationship (SAR) analysis to identify optimized inhibitors.

Main Methods:

• Development of a new synthetic route for the [4.3.1]-aza-bicyclic core scaffold.
• Preparation of an FKBP- and Mip-focused chemical library.
• Systematic SAR analysis across human FKBPs and microbial Mips.
• Cocrystallography to determine the molecular binding mode of the inhibitors.

Main Results:

• Highly improved inhibitors were identified for all studied FKBP targets.
• Cocrystal structure elucidated the binding mode and explained affinity enhancements from specific substituents.
• The most potent ligands demonstrated significant anti-infective activity in cellular models against Plasmodium falciparum, Legionella, and Chlamydia species.

Conclusions:

• C5-substituted [4.3.1]-aza-bicyclic sulfonamides represent a promising novel class of anti-infective agents.
• The developed synthetic strategy and SAR analysis provide a robust platform for designing potent FKBP and Mip inhibitors.
• These findings open new avenues for therapeutic strategies against infectious diseases targeted by FKBPs and Mips.