Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors

McGeachie, Andrew B., Odell, Luke R., Quan, Annie, Daniel, James A., Chau, Ngoc, Hill, Timothy A., Gorgani, Nick N., Keating, Damien J., Cousin, Michael A., van Dam, Ellen M., Mariana, Anna, Whiting, Ainslie, Perera, Swetha, Novelle, Aimee, Young, Kelly A., Deane, Fiona M., Gilbert, Jayne, Sakoff, Jennette A., Chircop, Megan, McCluskey, Adam and Robinson, Phillip J. (2013) Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors. ACS Chemical Biology, 8 7: 1507-1518. doi:10.1021/cb400137p


Author McGeachie, Andrew B.
Odell, Luke R.
Quan, Annie
Daniel, James A.
Chau, Ngoc
Hill, Timothy A.
Gorgani, Nick N.
Keating, Damien J.
Cousin, Michael A.
van Dam, Ellen M.
Mariana, Anna
Whiting, Ainslie
Perera, Swetha
Novelle, Aimee
Young, Kelly A.
Deane, Fiona M.
Gilbert, Jayne
Sakoff, Jennette A.
Chircop, Megan
McCluskey, Adam
Robinson, Phillip J.
Title Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors
Journal name ACS Chemical Biology   Check publisher's open access policy
ISSN 1554-8929
1554-8937
Publication date 2013-07-19
Year available 2013
Sub-type Article (original research)
DOI 10.1021/cb400137p
Open Access Status
Volume 8
Issue 7
Start page 1507
End page 1518
Total pages 12
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Subject 1303 Biochemistry
1313 Molecular Medicine
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.
Keyword Biochemistry & Molecular Biology
Biochemistry & Molecular Biology
BIOCHEMISTRY & MOLECULAR BIOLOGY
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 062841
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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