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Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors
Andrew B McGeachie1, Luke R Odell, Annie Quan
1Cell Signalling Unit, Children's Medical Research Institute, The University of Sydney , Sydney, NSW 2145, Australia.
ACS Chemical Biology
|May 7, 2013
Summary
Novel pyrimidine-based compounds called Pyrimidyns inhibit dynamin, a protein crucial for cellular endocytosis. These inhibitors block both GTP and lipid binding, offering a new tool for studying dynamin
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Dynamin is essential for clathrin-mediated endocytosis (CME).
- Its GTPase activity is regulated by phospholipid binding to its PH domain, promoting helical oligomerization.
Purpose of the Study:
- To design and characterize novel pyrimidine-based inhibitors targeting dynamin's GTPase activity.
- To investigate the mechanism of action of these inhibitors on dynamin function and endocytosis.
Main Methods:
- Design and synthesis of pyrimidine-based compounds (Pyrimidyns).
- Biochemical assays to measure dynamin GTPase activity and inhibition kinetics.
- Cell-based assays to assess inhibition of transferrin and EGF endocytosis, and synaptic vesicle endocytosis.
Main Results:
- Pyrimidyn compounds inhibit lipid-stimulated GTPase activity of dynamin I and II.
- Pyrimidyn 7 shows potent inhibition (IC50 of 1.1 μM for dynamin I, 1.8 μM for dynamin II).
- Pyrimidyn 7 competitively inhibits both GTP and phospholipid binding to dynamin I.
- Pyrimidyn 6 and 7 reversibly inhibit CME and synaptic vesicle endocytosis in various cell types.
Conclusions:
- Pyrimidyn compounds represent a novel class of dual-acting dynamin inhibitors.
- They block endocytosis by interfering with both GTP and lipid binding, limiting dynamin recruitment and activation.
- These compounds serve as valuable tools for dissecting dynamin's role in endocytosis.
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