Q&A: What Do Scientists Need to Learn Next About Blocking Enzymes to Treat Disease?

Why It Matters

Enzyme activation opens therapeutic avenues for diseases lacking effective treatments, expanding the drug‑discovery paradigm beyond inhibition.

Key Takeaways

• Enzyme activation far harder than inhibition
• VCP speed‑up achieved via gearbox‑binding compound
• 30,000‑compound screen yielded activator hits
• Approach may treat neurodegeneration and heart failure
• AI predicts structures but not dynamic enzyme motions

Pulse Analysis

For decades drug discovery has focused on blocking enzymes, a strategy that yields clear, binary outcomes and underpins many cancer and antiviral therapies. However, a growing body of research suggests that many pathologies stem from enzymes that work too slowly or inefficiently, creating a need for compounds that accelerate catalytic activity. Accelerating enzymes demands a deeper mechanistic understanding because the kinetic balance of cellular pathways can be easily disrupted. This shift from inhibition to activation is reshaping the therapeutic landscape.

Rockefeller’s Tarun Kapoor lab tackled this challenge by targeting VCP, an ATP‑driven protein‑sorting machine whose sluggish activity underlies a rare neurodegenerative disorder. An unbiased screen of roughly 30,000 drug‑like molecules identified several candidates that increased VCP turnover in vitro. Cryo‑EM revealed that the lead compound binds a previously uncharacterized “gearbox” region, nudging the enzyme into a higher‑gear conformation. Iterative chemistry refined potency, demonstrating that structural insight can translate directly into kinetic enhancement, a proof‑of‑concept for enzyme activation.

The VCP breakthrough illustrates a template that could be replicated across loss‑of‑function diseases, from other neurodegenerative conditions to heart‑failure enzymes currently in clinical trials. While AI tools such as AlphaFold excel at static structure prediction, they fall short of capturing the dynamic motions essential for designing activators, reinforcing the need for integrated biochemistry, structural biology, and proteomics. As the pharmaceutical industry embraces this activation paradigm, investors and biotech firms may see a new pipeline of precision medicines aimed at restoring, rather than suppressing, cellular function.