A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses.
Amino Acid Sequence
/ genetics
Amino Acids
/ genetics
Antigens, Viral
Antiviral Agents
Binding Sites
Capsid
/ drug effects
Capsid Proteins
/ metabolism
Cryoelectron Microscopy
/ methods
Drug Development
/ methods
Enterovirus
/ drug effects
Humans
Models, Molecular
Molecular Conformation
Rhinovirus
/ drug effects
Viral Proteins
/ chemistry
Virion
/ genetics
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
12
11
2018
accepted:
08
05
2019
entrez:
12
6
2019
pubmed:
12
6
2019
medline:
14
2
2020
Statut:
epublish
Résumé
Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens.
Identifiants
pubmed: 31185007
doi: 10.1371/journal.pbio.3000281
pii: PBIOLOGY-D-18-01199
pmc: PMC6559632
doi:
Substances chimiques
Amino Acids
0
Antigens, Viral
0
Antiviral Agents
0
Capsid Proteins
0
Viral Proteins
0
viral protein 1, rhinovirus
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3000281Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
J Struct Biol. 2016 Jan;193(1):1-12
pubmed: 26592709
Nat Protoc. 2010 Apr;5(4):725-38
pubmed: 20360767
Antimicrob Agents Chemother. 2014 Nov;58(11):6990-2
pubmed: 25199773
F1000Res. 2017 Oct 19;6:1860
pubmed: 29123648
J Comput Chem. 2005 Dec;26(16):1781-802
pubmed: 16222654
Virol J. 2015 Jul 14;12:106
pubmed: 26169596
Antiviral Res. 2014 Oct;110:1-9
pubmed: 25043639
J Mol Biol. 2007 Sep 21;372(3):774-97
pubmed: 17681537
Science. 1986 Sep 19;233(4770):1286-93
pubmed: 3018924
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
Sci Adv. 2016 Aug 24;2(8):e1501929
pubmed: 27574701
Clin Exp Vaccine Res. 2017 Jan;6(1):4-14
pubmed: 28168168
Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):8997-9002
pubmed: 27511920
Antimicrob Agents Chemother. 2009 May;53(5):1850-7
pubmed: 19237651
J Virol. 2012 Dec;86(23):12571-81
pubmed: 22973031
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
pubmed: 8744570
Vaccine. 2011 Dec 30;29 Suppl 4:D80-5
pubmed: 22486981
J Infect Dis. 2017 Feb 1;215(3):335-343
pubmed: 27932608
PLoS Pathog. 2014 Apr 10;10(4):e1004039
pubmed: 24722756
Antimicrob Agents Chemother. 1999 Sep;43(9):2109-15
pubmed: 10471549
Structure. 2008 May;16(5):673-83
pubmed: 18462672
Acta Crystallogr D Biol Crystallogr. 1995 Nov 1;51(Pt 6):871-87
pubmed: 15299757
J Struct Biol. 2015 Feb;189(2):114-22
pubmed: 25486611
J Virol. 2017 May 26;91(12):
pubmed: 28381577
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
Nat Struct Biol. 2001 Oct;8(10):874-8
pubmed: 11573093
Bioorg Chem. 2015 Oct;62:74-82
pubmed: 26247308
Lancet Infect Dis. 2016 May;16(5):e64-e75
pubmed: 26929196
Nat Rev Microbiol. 2018 Jun;16(6):368-381
pubmed: 29626210
J Virol. 1985 Sep;55(3):560-6
pubmed: 2991580
J Struct Biol. 2012 Dec;180(3):519-30
pubmed: 23000701