Inhibiting parasite proliferation using a rationally designed anti-tubulin agent.
anti-parasite
microtubules
rational structure-based drug design
species-specific tubulin inhibitor
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 11 2021
08 11 2021
Historique:
revised:
17
09
2021
received:
08
12
2020
accepted:
29
09
2021
pubmed:
19
10
2021
medline:
23
11
2021
entrez:
18
10
2021
Statut:
ppublish
Résumé
Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand-binding sites in tubulin makes this protein an attractive target for anti-parasite drug discovery. However, despite remarkable successes as anti-cancer agents, the rational development of protozoan parasite-specific tubulin drugs has been hindered by a lack of structural and biochemical information on protozoan tubulins. Here, we present atomic structures for a protozoan tubulin and microtubule and delineate the architectures of apicomplexan tubulin drug-binding sites. Based on this information, we rationally designed the parasite-specific tubulin inhibitor parabulin and show that it inhibits growth of parasites while displaying no effects on human cells. Our work presents for the first time the rational design of a species-specific tubulin drug providing a framework to exploit structural differences between human and protozoa tubulin variants enabling the development of much-needed, novel parasite inhibitors.
Identifiants
pubmed: 34661376
doi: 10.15252/emmm.202013818
pmc: PMC8573600
doi:
Substances chimiques
Antiparasitic Agents
0
Tubulin
0
Tubulin Modulators
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13818Subventions
Organisme : Wellcome Trust
ID : 202679/Z/16/Z
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/L014211/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R00352/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/N018176/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206166/Z/17/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 101311-10
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 217186/Z/19/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 079605/Z/06/Z
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : T32 AI141346
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R000352/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 104196/Z/14/Z
Pays : United Kingdom
Informations de copyright
© 2021 The Authors Published under the terms of the CC BY 4.0 license.
Références
Parasitology. 1997 Jan;114 ( Pt 1):1-6
pubmed: 9289695
J Struct Biol. 2015 Nov;192(2):245-54
pubmed: 26424086
J Mol Biol. 2014 Apr 17;426(8):1848-60
pubmed: 24530796
J Biol Chem. 2016 Jun 17;291(25):12907-15
pubmed: 27129203
Nat Rev Drug Discov. 2010 Oct;9(10):790-803
pubmed: 20885410
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
Cell. 2014 May 22;157(5):1117-29
pubmed: 24855948
Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12011-6
pubmed: 22778434
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
Dev Cell. 2016 Apr 4;37(1):72-84
pubmed: 27046833
Thyroid. 2009 Mar;19(3):233-40
pubmed: 19265494
Dev Cell. 2016 May 23;37(4):362-376
pubmed: 27219064
Methods Enzymol. 2010;482:167-83
pubmed: 20888961
EMBO J. 2003 May 1;22(9):2082-90
pubmed: 12727875
Elife. 2014 Aug 05;3:e03069
pubmed: 25097237
Genetics. 2008 Oct;180(2):845-56
pubmed: 18780736
J Struct Biol. 2007 Jan;157(1):38-46
pubmed: 16859925
Nat Rev Microbiol. 2018 Mar;16(3):156-170
pubmed: 29355852
Nat Rev Mol Cell Biol. 2015 Dec;16(12):711-26
pubmed: 26562752
J Struct Biol. 1999 Dec 1;128(1):82-97
pubmed: 10600563
ACS Infect Dis. 2020 Aug 14;6(8):2057-2072
pubmed: 32686409
Eukaryot Cell. 2010 Dec;9(12):1825-34
pubmed: 20870876
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):
pubmed: 28289248
J Comput Aided Mol Des. 1995 Jun;9(3):251-68
pubmed: 7561977
Nat Med. 2020 Oct;26(10):1602-1608
pubmed: 32747827
J Struct Biol. 2015 Nov;192(2):216-21
pubmed: 26278980
ChemMedChem. 2012 Jan 2;7(1):33-42
pubmed: 21990124
Mol Biol Cell. 2007 Dec;18(12):4711-20
pubmed: 17881728
Gynecol Oncol Res Pract. 2018 Jan 5;5:1
pubmed: 29318022
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
iScience. 2020 Aug 29;23(9):101511
pubmed: 32920486
Curr Biol. 2013 Dec 16;23(24):R1093-6
pubmed: 24355784
J Struct Biol. 2013 Sep;183(3):377-388
pubmed: 23872434
Mol Biochem Parasitol. 2001 Apr 6;113(2):309-13
pubmed: 11295185
FEBS J. 2016 Jan;283(1):102-11
pubmed: 26462166
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544
pubmed: 29872004
Eukaryot Cell. 2010 Nov;9(11):1680-9
pubmed: 20435700
EMBO Mol Med. 2021 Nov 8;13(11):e13818
pubmed: 34661376
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):133-44
pubmed: 20124693
Int J Mol Sci. 2017 Jun 22;18(7):
pubmed: 28640209
J Cell Sci. 2002 Mar 1;115(Pt 5):1017-25
pubmed: 11870220
Expert Opin Drug Discov. 2008 May;3(5):501-18
pubmed: 23484923
Methods Mol Biol. 2008;426:419-35
pubmed: 18542881
Trends Cell Biol. 2018 Oct;28(10):776-792
pubmed: 29871823
Proc Natl Acad Sci U S A. 2019 May 21;116(21):10366-10371
pubmed: 31072936
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Dev Cell. 2018 Oct 22;47(2):191-204.e8
pubmed: 30245157
Nature. 2004 Mar 11;428(6979):198-202
pubmed: 15014504
Methods Mol Biol. 2011;777:127-45
pubmed: 21773926
Eukaryot Cell. 2015 Jan;14(1):2-12
pubmed: 25380753