Le complexe terminase, une cible de choix dans le traitement de l’infection à cytomégalovirus humain

Ligat, Gaëtan; Muller, Clotilde; Alain, Sophie; Hantz, Sébastien

doi:10.1051/medsci/2020063

Cited by 3 publications

(5 citation statements)

References 63 publications

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“…The capsid structure of herpesviruses was resolved by cryo-electron microscopy, Figure 1. Different virus-like particles during the viral cycle of herpesviruses (adapted from [5,6]). After binding and entry into the host cell, the capsid is transported to the nuclear pore and delivers viral DNA into the nucleus.…”

Section: Assembly Of Herpesvirus Capsidsmentioning

confidence: 99%

“…(5) HCMV terminase proteins then perform a second cleavage, releasing viral DNA into the capsid via an interaction with pUL104 protein. (6) Finally, the complex is ready for the next DNA-packaging step (Figures 1 and 2). In general, terminase complexes are hetero-oligomers composed of three core proteins (pUL56, pUL89 and pUL51 for HCMV and pUL28, pUL15 and pUL33 for HSV-1), each carrying a different function required for the packaging process [30][31][32].…”

Section: Viral Dna Cleavage/packagingmentioning

confidence: 99%

“…Under the name Prevymis, letermovir was approved (August 2017) by the US Food and Drug Administration. Prevymis is indicated for the prophylaxis of HCMV reactivation and HCMV disease in HCMV-positive adults receiving [R+] allogeneic hematopoietic stem cell transplantation [5,6]. Whereas mutations associated with letermovir resistance map mainly to the pUL56, various letermovir resistance mutations in UL89 and UL51 have been identified [69][70][71][72].…”

Section: Inhibitors Of Terminase and Capsid Proteins For The Treatmenmentioning

confidence: 99%

“…It is indicated for the prophylaxis of HCMV reactivation and HCMV disease in HCMV-positive adults receiving allogeneic hematopoietic stem cell transplantation. However, this new drug has no significant activity against other herpesviruses or nonhuman CMV, and resistance mutations have already emerged [5,6]. Letermovir acts via a novel, not fully understood mechanism.…”

Section: Introductionmentioning

confidence: 99%

“…Letermovir acts via a novel, not fully understood mechanism. This drug inhibits the cleavage of viral DNA concatemers and the formation of mature HCMV virions by targeting the pUL56 subunit of the viral terminase complex [5,6]. Mutations associated with letermovir resistance map mainly to pUL56.…”

Section: Introductionmentioning

confidence: 99%

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Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses

Muller

Alain

Baumert

et al. 2021

Life

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Herpesviruses are the causative agents of several diseases. Infections are generally mild or asymptomatic in immunocompetent individuals. In contrast, herpesvirus infections continue to contribute to significant morbidity and mortality in immunocompromised patients. Few drugs are available for the treatment of human herpesvirus infections, mainly targeting the viral DNA polymerase. Moreover, no successful therapeutic options are available for the Epstein–Barr virus or human herpesvirus 8. Most licensed drugs share the same mechanism of action of targeting the viral polymerase and thus blocking DNA polymerization. Resistances to antiviral drugs have been observed for human cytomegalovirus, herpes simplex virus and varicella-zoster virus. A new terminase inhibitor, letermovir, recently proved effective against human cytomegalovirus. However, the letermovir has no significant activity against other herpesviruses. New antivirals targeting other replication steps, such as capsid maturation or DNA packaging, and inducing fewer adverse effects are therefore needed. Targeting capsid assembly or DNA packaging provides additional options for the development of new drugs. In this review, we summarize recent findings on capsid assembly and DNA packaging. We also described what is known about the structure and function of capsid and terminase proteins to identify novels targets for the development of new therapeutic options.

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Section: Assembly Of Herpesvirus Capsidsmentioning

confidence: 99%

Section: Viral Dna Cleavage/packagingmentioning

confidence: 99%

Section: Inhibitors Of Terminase and Capsid Proteins For The Treatmenmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses

Muller

Alain

Baumert

et al. 2021

Life

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Letermovir use to treat complex cytomegalovirus reactivations in two heart transplant recipients

et al. 2022

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Letermovir, an anti-cytomegalovirus (CMV) drug, is recommended as a prophylactic agent in patients at risk of CMV infection/reactivation after allogeneic hematopoietic stem cell transplant. We report the curative and pre-emptive use of letermovir in two heart transplant recipients. In one patient with ganciclovir-resistant CMV, letermovir was successfully used to treat CMV colitis. In the second patient, letermovir was used as pre-emptive therapy for CMV reactivation, but did not prevent CMV esophagitis. In both cases, letermovir was successful for secondary prophylaxis. Curative use of letermovir may be considered if resistance or major adverse effect of other antivirals therapy is suspected.

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Challenges, Recent Advances and Perspectives in the Treatment of Human Cytomegalovirus Infections

2022

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Human cytomegalovirus (HCMV) is ubiquitous worldwide and elicits global health problems. The diseases associated with HCMV are a serious threat to humans, especially for the sick, infant, elderly and immunocompromised/immunodeficient individuals. Although traditional antiviral drugs (e.g., ganciclovir, valganciclovir, cidofovir, foscarnet) can be used to treat or prevent acute HCMV infections, their efficacy is limited because of toxicity, resistance issues, side effects and other problems. Fortunately, novel drugs (e.g., letermovir and maribavir) with less toxicity and drug/cross-resistance have been approved and put on the market in recent years. The nucleic acid-based gene-targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPRs)/CRISPRs-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) have been investigated to remove both lytic and latent CMV in vitro and/or in vivo. Cell therapy including the adoptive T cell therapy (ACT) and immunotherapy have been tried against drug-resistant and recurrent HCMV in patients receiving hematopoietic stem cell transplantation (HSCT) or solid organ transplant (SOT), and they have also been used to treat glioblastoma (GBM) associated with HCMV infections. These newly developed antiviral strategies are expected to yield fruitful results and make a significant contribution to the treatment of HCMV infections. Despite this progress, the nucleic acid-based gene-targeting approaches are still under study for basic research, and cell therapy is adopted in a small study population size or only successful in case reports. Additionally, no current drugs have been approved to be indicated for latent infections. Therefore, the next strategy is to develop antiviral strategies to elevate efficacy against acute and/or latent infections and overcome challenges such as toxicity, resistance issues, and side effects. In this review, we would explore the challenges, recent advances and perspectives in the treatment of HCMV infections. Furthermore, the suitable therapeutic strategies as well as the possibility for compassionate use would be evaluated.

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Le complexe terminase, une cible de choix dans le traitement de l’infection à cytomégalovirus humain

Cited by 3 publications

References 63 publications

Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses

Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses

Letermovir use to treat complex cytomegalovirus reactivations in two heart transplant recipients

Challenges, Recent Advances and Perspectives in the Treatment of Human Cytomegalovirus Infections

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