Design, synthesis, and anti-inflammatory potential of PROTAC drug molecules based on fondaparinux sodium
Ruoxuan Wu, Tianji Zhang, Siran Zhao, Marco Maccarana, Jin-Ping Li, Chao Li, Hui Cao
TL;DR
This study creates and tests new anti-inflammatory drug molecules called PROTACs based on fondaparinux sodium, showing they can inhibit inflammation effectively.
Contribution
The paper introduces a scalable method to synthesize high-purity PROTACs with anti-inflammatory potential.
Findings
High-purity (>99%) PROTAC molecules were produced using a scalable platform.
Two candidate compounds significantly inhibited LPS-induced IL-1β release in PBMCs.
PROTACs showed micromolar binding affinities toward RANTES (CCL5) and IL-6.
Abstract
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.…
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Taxonomy
TopicsProtein Degradation and Inhibitors · Multiple Myeloma Research and Treatments · Peptidase Inhibition and Analysis