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Discovery of Small-Molecule CD33 Pre-mRNA Splicing Modulators
Thomas A Chappie1, Mario Abdelmessih2, Claude W Ambroise3
1Internal Medicine Medicinal Chemistry, Pfizer, Inc., Cambridge, Massachusetts 02139, United States.
ACS Medicinal Chemistry Letters
|January 21, 2022
Summary
Researchers identified compounds that modify CD33 alternative splicing, reducing Alzheimer's disease risk. This work offers a new approach to targeting neuroimmune function in neurodegenerative diseases.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Genetics
Background:
- CD33 (Siglec 3) is a myeloid cell receptor regulating microglia activity.
- Genetic variants in CD33 are linked to protection from late-onset Alzheimer's disease.
- Disease protection is associated with alternative splicing of CD33 exon 2.
Purpose of the Study:
- To identify small molecules that modulate CD33 pre-mRNA splicing.
- To develop chemomimetics for Alzheimer's disease-protective CD33 variants.
- To explore pharmacological interventions for neuroimmune function in neurodegenerative diseases.
Main Methods:
- Phenomimetic screening to identify compounds enhancing CD33 exon 2 exclusion.
- Treatment of myeloid lineage cells with identified compounds.
- Analysis of CD33 protein levels and targeted RNA-sequencing to confirm splicing modulation.
Main Results:
- Several compounds were identified that enhance CD33 exon 2 skipping.
- Compound 1 effectively increased exon 2 skipping in cellular mRNA.
- Treated myeloid cells showed reduced levels of full-length CD33 protein.
Conclusions:
- Pharmacological manipulation of disease-relevant pre-mRNA splicing is feasible.
- Small molecules can alter neuroimmune function by targeting CD33 splicing.
- This study provides a foundation for developing novel therapeutics for neurodegenerative diseases.
