Brian Kobilka

Helene Irwin Fagan Chair of Cardiology, Stanford University. Nobel Prize in Chemistry, 2012 — for studies of G-protein-coupled receptors (GPCRs). Panelist at Session XII.

Key Work: Allosteric Modulators for the Mu-Opioid Receptor

GPCRs are the target of ~35-40% of all approved drugs, encoded by ~800 human genes. Drug discovery has disappointed because the orthosteric pocket is too similar across receptor subfamilies.

The Mu-Opioid Receptor Problem

• The receptor couples to six G-protein isoforms plus arrestin — some for analgesia, others for respiratory depression, addiction, constipation
• Allosteric modulators can selectively shift this signaling balance

Negative Allosteric Modulator

• From 4-billion-compound DEL screen
• Dramatically extends naloxone’s duration — addressing fentanyl outlasting emergency naloxone

Positive Allosteric Modulator (AP58)

• From 40-billion-compound screen
• Produces dose-dependent pain relief without exogenous opioid — amplifies endogenous met-enkephalin
• No addiction signal in conditioned place preference
• Preserves temporal regulation of analgesic signaling

“Allosteric modulators really only work when the body is naturally activating these receptors with endogenous opiates.”

Advice

• Spent 16 years trying to crystallize GPCRs with near-constant failure
• “Troubleshoot before you run the experiment”