[The terminase complex, a relevant target for the treatment of HCMV infection].
Le complexe terminase, une cible de choix dans le traitement de l’infection à cytomégalovirus humain.
Antiviral Agents
/ therapeutic use
Cytomegalovirus
/ pathogenicity
Cytomegalovirus Infections
/ drug therapy
Endodeoxyribonucleases
/ antagonists & inhibitors
Humans
Immunocompromised Host
Molecular Targeted Therapy
/ methods
Multiprotein Complexes
/ antagonists & inhibitors
Virus Assembly
/ drug effects
Virus Replication
/ drug effects
Journal
Medecine sciences : M/S
ISSN: 1958-5381
Titre abrégé: Med Sci (Paris)
Pays: France
ID NLM: 8710980
Informations de publication
Date de publication:
Apr 2020
Apr 2020
Historique:
entrez:
2
5
2020
pubmed:
2
5
2020
medline:
2
10
2020
Statut:
ppublish
Résumé
Human cytomegalovirus (HCMV) is an important ubiquitous opportunistic pathogen that belongs to the betaherpesviridae. Primary HCMV infection is generally asymptomatic in immunocompetent individuals. In contrast, HCMV infection causes serious disease in immunocompromised patients and is the leading cause of congenital viral infection. Although they are effective, the use of conventional molecules is limited by the emergence of resistance and by their toxicity. New antivirals targeting other replication steps and inducing fewer adverse effects are therefore needed. During HCMV replication, DNA packaging is performed by the terminase complex, which cleaves DNA to package the virus genome into the capsid. With no counterpart in mammalian cells, these terminase proteins are ideal targets for highly specific antivirals. A new terminase inhibitor, letermovir, recently proved effective against HCMV in phase III clinical trials. However, its mechanism of action is unclear and it has no significant activity against other herpesvirus or non-human CMV. Le complexe terminase, une cible de choix dans le traitement de l’infection à cytomégalovirus humain. Le cytomégalovirus humain (CMVH) est un pathogène opportuniste majeur en cas d’immunodépression et représente la principale cause d’infection congénitale d’origine virale. Bien qu’efficace, l’utilisation des molécules conventionnelles est limitée par leur toxicité et par l’émergence de résistance du virus, rendant nécessaire le développement de nouveaux traitements. Lors de la réplication du CMVH, l’encapsidation de l’ADN est réalisée par le complexe terminase qui clive l’ADN pour empaqueter le génome dans la capside. L’absence d’homologues dans les cellules des mammifères rend les protéines du complexe terminase des cibles idéales pour des antiviraux spécifiques. Une nouvelle molécule, le letermovir, cible une étape exclusivement virale en interagissant avec le complexe terminase. Son efficacité a été prouvée lors d’essais cliniques de phase III. Néanmoins, son mécanisme d’action n’est, à ce jour, pas élucidé et aucune activité n’est observée contre les autres herpèsvirus.
Autres résumés
Type: Publisher
(fre)
Le complexe terminase, une cible de choix dans le traitement de l’infection à cytomégalovirus humain.
Identifiants
pubmed: 32356713
doi: 10.1051/medsci/2020063
pii: msc190286
doi:
Substances chimiques
Antiviral Agents
0
Multiprotein Complexes
0
Endodeoxyribonucleases
EC 3.1.-
terminase
EC 3.1.-
Types de publication
Journal Article
Review
Langues
fre
Sous-ensembles de citation
IM
Pagination
367-375Informations de copyright
© 2020 médecine/sciences – Inserm.
Références
Rubin RH . Prevention of cytomegalovirus infection in organ transplant recipients. Transpl Infect Dis 2000 ; 2 : 99–100.
Pereyra F , Rubin RH . Prevention and treatment of cytomegalovirus infection in solid organ transplant recipients. Curr Opin Infect Dis 2004 ; 17 : 357–361.
Andouard D , Mazeron MC , Ligat G , et al. Contrasting effect of new HCMV pUL54 mutations on antiviral drug susceptibility: Benefits and limits of 3D analysis. Antiviral Res 2016 ; 129 : 115–119.
Leruez-Ville M, Ghout I, Bussières L, et al. In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study. Am J Obstet Gynecol 2016; 215 : 462.e1-e10.
McVoy MA , Adler SP . Human cytomegalovirus DNA replicates after early circularization by concatemer formation, and inversion occurs within the concatemer. J Virol 1994 ; 68 : 1040–1051.
Scheffczik H , Savva CGW , Holzenburg A , et al. The terminase subunits pUL56 and pUL89 of human cytomegalovirus are DNA-metabolizing proteins with toroidal structure. Nucleic Acids Res 2002 ; 30 : 1695–1703.
Borst EM , Kleine-Albers J , Gabaev I , et al. The human cytomegalovirus UL51 protein is essential for viral genome cleavage-packaging and interacts with the terminase subunits pUL56 and pUL89. J Virol 2013 ; 87 : 1720–1732.
Borst EM , Wagner K , Binz A , et al. The essential human cytomegalovirus gene UL52 is required for cleavage-packaging of the viral genome. J Virol 2008 ; 82 : 2065–2078.
Borst EM , Bauerfeind R , Binz A , et al. The Essential human cytomegalovirus proteins pUL77 and pUL93 are structural components necessary for viral genome encapsidation. J Virol 2016 ; 90 : 5860–5875.
DeRussy BM , Tandon R . Human cytomegalovirus pUL93 is required for viral genome cleavage and packaging. J Virol 2015 ; 89 : 12221–12225.
Köppen-Rung P , Dittmer A , Bogner E . Intracellular distributions of capsid-associated pUL77 of HCMV and interactions with packaging proteins and pUL93. J Virol 2016 ; 90 : 5876–5885.
DeRussy BM , Tandon R . Human cytomegalovirus pUL93 is required for viral genome cleavage and packaging. J Virol 2015 ; 89 : 12221–12225.
Bogner E. . Human cytomegalovirus terminase as a target for antiviral chemotherapy. Rev Med Virol 2002 ; 12 : 115–127.
Champier G , Couvreux A , Hantz S , et al. Putative functional domains of human cytomegalovirus pUL56 involved in dimerization and benzimidazole D-ribonucleoside activity. Antivir Ther 2008 ; 13 : 643–654.
Addison C , Rixon FJ , Preston VG . Herpes simplex virus type 1 UL28 gene product is important for the formation of mature capsids. J GenVirol 1990 ; 71 : 2377–2384.
Bogner E , Reschke M , Reis B , et al. Identification of the gene product encoded by ORF UL56 of the human cytomegalovirus genome. Virology 1993 ; 196 : 290–293.
Savva CGW , Holzenburg A , Bogner E . Insights into the structure of human cytomegalovirus large terminase subunit pUL56. FEBS Lett 2004 ; 563 : 135–140.
Hwang J-S , Bogner E . ATPase activity of the terminase subunit pUL56 of human cytomegalovirus. J Biol Chem 2002 ; 277 : 6943–6948.
Bogner E , Radsak K , Stinski MF . The gene product of human cytomegalovirus open reading frame UL56 binds the pac motif and has specific nuclease activity. J Virol 1998 ; 72 : 2259–2264.
Giesen K , Radsak K , Bogner E . Targeting of the gene product encoded by ORF UL56 of human cytomegalovirus into viral replication centers. FEBS Lett 2000 ; 471 : 215–218.
Neuber S, Wagner K, Goldne T, et al. Mutual interplay between the human cytomegalovirus terminase subunits pUL51, pUL56, and pUL89 promotes terminase complex formation. J Virol 2017; 91. pii: e02384–16.
Thoma C , Borst E , Messerle M , et al. Identification of the interaction domain of the small terminase subunit pUL89 with the large subunit pUL56 of human cytomegalovirus. Biochemistry 2006 ; 45 : 8855–8863.
Ligat G , Jacquet C , Chou S , et al. Identification of a short sequence in the HCMV terminase pUL56 essential for interaction with pUL89 subunit. Sci Rep 2017 ; 7 : 8796.
Scholz B , Rechter S , Drach JC , et al. Identification of the ATP-binding site in the terminase subunit pUL56 of human cytomegalovirus. Nucleic Acids Res 2003 ; 31 : 1426–1433.
Ligat G, Couvreux A, Cazal R, et al. Highlighting of a LAGLIDADG and a zing finger motifs located in the pUL56 sequence crucial for HCMV replication. Viruses 2019; 11.
Champier G , Hantz S , Couvreux A , et al. New functional domains of human cytomegalovirus pUL89 predicted by sequence analysis and three-dimensional modelling of the catalytic site DEXDc. Antivir Ther 2007 ; 12 : 217–232.
Couvreux A , Hantz S , Marquant R , et al. Insight into the structure of the pUL89 C-terminal domain of the human cytomegalovirus terminase complex. Proteins 2010 ; 78 : 1520–1530.
Nadal M , Mas PJ , Blanco AG , et al. Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain. Proc Natl Acad Sci USA 2010 ; 107 : 16078–16083.
Wang JB , Zhu Y , McVoy MA , et al. Changes in subcellular localization reveal interactions between human cytomegalovirus terminase subunits. Virol J 2012 ; 9 : 315.
Neuber S , Wagner K , Messerle M , et al. The C-terminal part of the human cytomegalovirus terminase subunit pUL51 is central for terminase complex assembly. J Gen Virol 2017 ; 99 : 119–134.
Borst EM , Wagner K , Binz A , et al. The essential human cytomegalovirus gene UL52 is required for cleavage-packaging of the viral genome. J Virol 2008 ; 82 : 2065–2078.
DeRussy BM , Boland MT , Tandon R . Human cytomegalovirus pUL93 links nucleocapsid maturation and nuclear egress. J Virol 2016 ; 90 : 7109–7117.
Ligat G , Cazal R , Hantz S , et al. The human cytomegalovirus terminase complex as an antiviral target: a close-up view. FEMS Microbiol Rev 2018 ; 42 : 137–145.
Goldner T , Hewlett G , Ettischer N , et al. The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol 2011 ; 85 : 10884–10893.
Lischka P , Hewlett G , Wunberg T , et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob. Agents Chemother 2010 ; 54 : 1290–1297.
Stoelben S , Arns W , Renders L , et al. Preemptive treatment of cytomegalovirus infection in kidney transplant recipients with letermovir: results of a phase 2a study. Transplant 2014 ; 27 : 77–86.
Chemaly RF , Ullmann AJ , Stoelben S , et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med 2014 ; 370 : 1781–1789.
Piret J, Goyette N, Boivin G. Drug susceptibility and replicative capacity of multi-drug resistant recombinant human cytomegalovirus harboring mutations in UL56 and UL54 genes. Antimicrob Agents Chemother 2017; 61. pii: e01044–17.
Goldner T , Hempel C , Ruebsamen-Schaeff H , et al. Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure. Antimicrob. Agents Chemother 2014 ; 58 : 610–613.
Chou S. . Comparison of cytomegalovirus terminase gene mutations selected after exposure to three distinct inhibitor compounds. Antimicrob Agents Chemother 2017 ; 61.
Chou S . A third component of the human cytomegalovirus terminase complex is involved in letermovir resistance. Antiviral Res 2017 ; 148 : 1–4.
Komatsu TE , Hodowanec AC , Colberg-Poley AM , et al. In-depth genomic analyses identified novel letermovir resistance-associated substitutions in the cytomegalovirus UL56 and UL89 gene products. Antiviral Res 2019 ; 169 : 104549.
Douglas CM, Barnard R, Holder D, et al. Letermovir resistance analysis in a clinical trial of cytomegalovirus prophylaxis for hematopoietic stem cell transplant recipients. J Infect Dis 2019; pii: jiz577.
Marschall M , Stamminger T , Urban A , et al. In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses. Antimicrob. Agents Chemother 2012 ; 56 : 1135–1137.
Champier G , Couvreux A , Hantz S , et al. Putative functional domains of human cytomegalovirus pUL56 involved in dimerization and benzimidazole D-ribonucleoside activity. Antivir Ther 2008 ; 13 : 643–654.
Lischka P , Michel D , Zimmermann H . Characterization of cytomegalovirus breakthrough events in a letermovir (AIC246, MK 8228) phase 2 prophylaxis trial. J Infect Dis 2015 ; 213 : 23–30.
Goldner T , Hempel C , Ruebsamen-Schaeff H , et al. Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure. Antimicrob Agents Chemother 2014 ; 58 : 610–613.
Vial R , Zandotti C , Alain S , et al. Brincidofovir use after foscarnet crystal nephropathy in a kidney transplant recipient with multiresistant cytomegalovirus infection. Case Rep Transplant 2017 ; 2017 : 3624146.
Marty FM , Winston DJ , Chemaly RF , et al. A randomized, double-blind, placebo-controlled phase 3 trial of oral brincidofovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2019 ; 25 : 369–381.
Kaptein SJF , Efferth T , Leis M , et al. The anti-malaria drug artesunate inhibits replication of cytomegalovirus in vitro and in vivo. Antiviral Res 2006 ; 69 : 60–69.
Chou S , Marousek G , Auerochs S , et al. The unique antiviral activity of artesunate is broadly effective against human cytomegaloviruses including therapy-resistant mutants. Antiviral Res 2011 ; 92 : 364–368.
Germi R , Mariette C , Alain S , et al. Success and failure of artesunate treatment in five transplant recipients with disease caused by drug-resistant cytomegalovirus. Antiviral Res 2014 ; 101 : 57–61.
Wolf DG , Shimoni A , Resnick IB , et al. Human cytomegalovirus kinetics following institution of artesunate after hematopoietic stem cell transplantation. Antiviral Res 2011 ; 90 : 183–186.
Lyss G , Knorre A , Schmidt TJ , et al. The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65. J Biol Chem 1998 ; 273 : 33508–33516.
Hutterer C , Niemann I , Milbradt J , et al. The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-κB) pathway by targeting RelA/p65. Antiviral Res 2015 ; 124 : 101–109.
Koszalka GW , Johnson NW , Good SS , et al. Preclinical and toxicology studies of 1263W94, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother 2002 ; 46 : 2373–2380.
Marty FM , Ljungman P , Papanicolaou GA , et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis 2011 ; 11 : 284–292.
Alain S , Revest M , Veyer D , et al. Maribavir use in practice for cytomegalovirus infection in French transplantation centers. Transplant Proc 2013 ; 45 : 1603–1607.
Papanicolaou GA , Silveira FP , Langston AA , et al. Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study. Clin Infect Dis 2019 ; 68 : 1255–1264.
Ligat G , Da Re S , Alain S , et al. Identification of amino acids essential for viral replication in the HCMV helicase-primase complex. Front Microbiol 2018 ; 9 : 2483.