Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/99314
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Type: Journal article
Title: Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors
Author: McGeachie, A.
Odell, L.
Quan, A.
Daniel, J.
Chau, N.
Hill, T.
Gorgani, N.
Keating, D.
Cousin, M.
van Dam, E.
Mariana, A.
Whiting, A.
Perera, S.
Novelle, A.
Young, K.
Deane, F.
Gilbert, J.
Sakoff, J.
Chircop, M.
McCluskey, A.
et al.
Citation: ACS Chemical Biology, 2013; 8(7):1507-1518
Publisher: American Chemical Society
Issue Date: 2013
ISSN: 1554-8929
1554-8937
Statement of
Responsibility: 
Andrew B. McGeachie, Luke R. Odell, Annie Quan, James A. Daniel, Ngoc Chau, Timothy A. Hill, Nick N. Gorgani, Damien J. Keating, Michael A. Cousin, Ellen M. van Dam, Anna Mariana, Ainslie Whiting, Swetha Perera, Aimee Novelle, Kelly A. Young, Fiona M. Deane, Jayne Gilbert, Jennette A. Sakoff, Megan Chircop, Adam McCluskey, and Phillip J. Robinson
Abstract: Dynamin is required for clathrin-mediated endocytosis (CME). Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization. We have designed a series of novel pyrimidine-based “Pyrimidyn” compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency. The most potent analogue, Pyrimidyn 7, has an IC50 of 1.1 μM for dynamin I and 1.8 μM for dynamin II, making it among the most potent dynamin inhibitors identified to date. We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin. The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin. Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals. Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation. This dual mode of action provides an important new tool for molecular dissection of dynamin’s role in endocytosis.
Keywords: COS Cells; Animals; Cercopithecus aethiops; Pyrimidines; Dynamins; Blotting, Western; Biological Assay; Flow Cytometry; Endocytosis; Molecular Structure; Protein Binding; Drug Design; Small Molecule Libraries
Rights: © 2013 American Chemical Society
RMID: 0020131530
DOI: 10.1021/cb400137p
Appears in Collections:Medicine publications

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