Hijacking Nature’s Recycling System to Target a Key Immune Enzyme
Researchers have developed a new class of drug-like molecules, called iDegs, that not only inhibit but also destroy the immunomodulatory enzyme IDO1. Unlike conventional targeted protein degraders that hijack an external E3 ligase, these monovalent compounds, derived from a natural product scaffold, uniquely exploit the enzyme’s own native degradation pathway. By binding to the inactive, “apo” form of IDO1, iDegs prime it for ubiquitination and subsequent disposal by the cell’s proteasome, offering a potentially more selective therapeutic strategy.
Why it might matter to you:
This work demonstrates a novel mechanistic approach in the targeted protein degradation field, moving beyond heterobifunctional degraders. For a medicinal chemist, the discovery of monovalent, pseudo-natural product “degraders” that co-opt a target’s endogenous E3 ligase could open new avenues for drug design, potentially improving selectivity and reducing off-target effects. It provides a compelling case study for leveraging native protein homeostasis machinery, a concept that could be applied to other challenging therapeutic targets beyond IDO1.
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