Design, synthesis, and anti-inflammatory potential of PROTAC drug molecules based on fondaparinux sodium

In this study, we used an approach by conjugating Fondaparinux Sodium (FS) with selected drugs to generate proteolysis-targeting chimeras (PROTACs).

By applying bioprocess engineering principles, the direct amidation reaction was optimized -through precise control of pH, substrate ratios, and solvent selection -to reliably produce high-purity (>99%) PROTAC molecules on a scalable platform. Surface plasmon resonance (SPR) analysis demonstrated that the synthesized PROTACs exhibit micromolar binding affinities (KD ≈ 10^-6 M) toward inflammatory mediators RANTES (CCL5) and interleukin-6 (IL-6). In vitro assays using peripheral blood mononuclear cells (PBMCs) revealed that two candidate compounds (Product 6 and Product 10) significantly inhibited lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) release in a concentration-dependent manner, while FS and the drugs alone had no effect.

High-purity (>99%) PROTAC molecules were produced on a scalable platform. The synthesized PROTACs demonstrated micromolar binding affinities (KD ≈ 10^-6 M) toward RANTES (CCL5) and IL-6. Two candidate compounds (Product 6 and Product 10) significantly inhibited LPS-induced IL-1β release in PBMCs in a concentration-dependent manner; FS and the drugs alone showed no effect.

These findings not only provide an innovative strategy for targeting "undruggable" proteins but also establish a robust, scalable process for the production of PROTAC-based anti-inflammatory agents.