A chemical method for generating live-attenuated, replication-defective DNA viruses for vaccine development.
CM
DNA viruses
centanamycin
cytomegalovirus
herpes simplex virus
inactivated viruses
live-attenuated viruses
vaccines
Journal
Cell reports methods
ISSN: 2667-2375
Titre abrégé: Cell Rep Methods
Pays: United States
ID NLM: 9918227360606676
Informations de publication
Date de publication:
19 09 2022
19 09 2022
Historique:
received:
26
01
2022
revised:
22
06
2022
accepted:
17
08
2022
entrez:
26
9
2022
pubmed:
27
9
2022
medline:
27
9
2022
Statut:
epublish
Résumé
The development of a chemically attenuated, replication-incompetent virus vaccine can provide protection against diseases caused by DNA viruses. In this study, we have developed a method to produce live-attenuated, replication-defective viruses using centanamycin (CM), a chemical compound that alkylates the A-T-rich minor groove of the DNA and thereby blocks DNA replication. We tested the efficacy of CM to produce live-attenuated, replication-defective human cytomegalovirus, mouse cytomegalovirus, and herpes simplex virus-2 (HSV-2), suggesting a broad application for generating live-attenuated, replication-defective DNA viruses. Mass spectrometry analysis showed that CM alkylate viral DNA at the adenine-N3 position. Moreover, mice immunization with CM-attenuated mouse cytomegalovirus (MCMV) produced a robust immune response and reduced the viral load in immunized animals against challenges with live, wild-type MCMV. Our study offers a unifying and attractive therapeutic opportunity that chemically attenuated live DNA viruses can be readily developed as new frontline vaccines.
Identifiants
pubmed: 36160049
doi: 10.1016/j.crmeth.2022.100287
pii: S2667-2375(22)00169-2
pmc: PMC9499982
doi:
Substances chimiques
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Pagination
100287Subventions
Organisme : NHLBI NIH HHS
ID : U01 HL150852
Pays : United States
Déclaration de conflit d'intérêts
United States and worldwide patents have been filed based on the research findings in this paper.
Références
Biomed Imaging Interv J. 2006 Jul;2(3):e7
pubmed: 21614253
Cancer Chemother Pharmacol. 2012 Jun;69(6):1423-31
pubmed: 22367116
J Virol Methods. 2009 May;157(2):180-7
pubmed: 19162076
Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):E7082-E7091
pubmed: 28784758
Adv Exp Med Biol. 2021;1313:1-14
pubmed: 34661888
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11321-6
pubmed: 8876134
Int J Cancer. 2006 Jun 15;118(12):3030-44
pubmed: 16404738
J Infect Dis. 2019 Jul 2;220(3):411-419
pubmed: 31535143
J Med Chem. 2005 Jun 2;48(11):3903-18
pubmed: 15916443
Oncogene. 2007 Feb 26;26(9):1297-305
pubmed: 17322915
Biol Blood Marrow Transplant. 2012 Nov;18(11):1700-8
pubmed: 22641196
Virology. 1997 May 26;232(1):1-12
pubmed: 9185583
Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8427-32
pubmed: 26080445
Virology. 2005 Oct 10;341(1):91-101
pubmed: 16061267
N Engl J Med. 1987 Jun 18;316(25):1607-8
pubmed: 3035374
Science. 2008 Feb 22;319(5866):1096-100
pubmed: 18202256
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3642-9
pubmed: 7731958
Lancet. 2007 Sep 8;370(9590):890-907
pubmed: 17826171
Geburtshilfe Frauenheilkd. 2016 Dec;76(12):1310-1317
pubmed: 28017972
Virology. 1996 Jun 15;220(2):402-13
pubmed: 8661391
Bioorg Med Chem Lett. 2018 May 1;28(8):1342-1347
pubmed: 29548574
BMC Med. 2018 Oct 8;16(1):184
pubmed: 30293531
J Virol. 2007 Sep;81(17):9024-33
pubmed: 17581997
Biochemistry. 1991 Jul 30;30(30):7559-65
pubmed: 1854754
J Virol. 2018 Jul 31;92(16):
pubmed: 29899091
J Virol. 2005 Jan;79(1):410-8
pubmed: 15596834
Sci Transl Med. 2016 Oct 26;8(362):362ra145
pubmed: 27797961
Sci Rep. 2017 Jan 27;7:41324
pubmed: 28128222
J Virol. 2002 Jan;76(2):767-73
pubmed: 11752166
J Infect Dis. 2008 Feb 15;197(4):527-34
pubmed: 18275274
J Virol. 2019 Nov 13;93(23):
pubmed: 31511385
Infect Immun. 2008 Mar;76(3):1193-9
pubmed: 18174336
Science. 1994 Dec 16;266(5192):1865-9
pubmed: 7997879