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Author Spotlight: Development of a Method for Identifying Small Molecular Antagonists of β2 Integrin Activation
Published on: February 2, 2024
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A general chemical principle for creating closure-stabilizing integrin inhibitors
Fu-Yang Lin1, Jing Li1, Yonghua Xie2
1Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell
|September 16, 2022
Summary
Small-molecule integrin inhibitors can fail by stabilizing active conformations. A newly identified chemical feature, a polar nitrogen atom, can instead stabilize inactive integrin conformations, offering a new drug design strategy.
Area of Science:
- Biochemistry
- Pharmacology
- Structural Biology
Background:
- Integrins are crucial drug targets, with approved therapies available.
- Previous small-molecule inhibitors for integrins (αIIbβ3, α4β1) failed in late-stage trials for chronic conditions.
- Partial agonism, stabilizing high-affinity integrin states, is a potential cause of these failures.
Purpose of the Study:
- To investigate why certain small-molecule integrin inhibitors failed in clinical trials.
- To identify structural mechanisms underlying integrin inhibition.
- To discover novel drug design principles for developing effective integrin antagonists.
Main Methods:
- Biochemical assays to assess integrin conformation.
- Structural analysis of small-molecule inhibitors bound to integrins.
- Structure-activity relationship studies to identify key chemical features.
Main Results:
- Failed small-molecule inhibitors of integrins αIIbβ3 and α4β1 were found to stabilize the high-affinity, extended-open conformation.
- A novel chemical feature (polar nitrogen atom) in αIIbβ3 antagonists was identified that stabilizes the bent-closed, low-affinity conformation.
- This stabilization involves a water molecule in the metal-ion-dependent adhesion site (MIDAS), preventing transition to the open state.
Conclusions:
- Partial agonism by stabilizing active conformations contributes to the failure of some integrin inhibitors.
- A simple chemical feature, a polar nitrogen, can be exploited to design inhibitors that stabilize the inactive integrin conformation.
- This drug design principle shows broad applicability across the integrin family, as demonstrated with α4β1 integrin.
Keywords:
agonismautoimmune diseaseconformation specificityconformational changeconformationsdrug discoveryhydrogen bondsintegrin inhibitorsintegrinsmembrane receptorsthrombosisα4β1αIIbβ3More Related Videos
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