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New Insights into Human Cytomegalovirus pUL52 Structure

Human cytomegalovirus (HCMV) can cause serious diseases in immunocompromised patients. Current antiviral inhibitors all target the viral DNA polymerase. They have adverse effects, and prolonged treatment can select for drug resistance mutations. Thus, new drugs targeting other stages of replication...

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Autores principales: Muller, Clotilde, Alain, Sophie, Gourin, Claire, Baumert, Thomas F., Ligat, Gaëtan, Hantz, Sébastien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402748/
https://www.ncbi.nlm.nih.gov/pubmed/34452502
http://dx.doi.org/10.3390/v13081638
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author Muller, Clotilde
Alain, Sophie
Gourin, Claire
Baumert, Thomas F.
Ligat, Gaëtan
Hantz, Sébastien
author_facet Muller, Clotilde
Alain, Sophie
Gourin, Claire
Baumert, Thomas F.
Ligat, Gaëtan
Hantz, Sébastien
author_sort Muller, Clotilde
collection PubMed
description Human cytomegalovirus (HCMV) can cause serious diseases in immunocompromised patients. Current antiviral inhibitors all target the viral DNA polymerase. They have adverse effects, and prolonged treatment can select for drug resistance mutations. Thus, new drugs targeting other stages of replication are an urgent need. The terminase complex (pUL56–pUL89–pUL51) is highly specific, has no counterpart in the human organism, and thus represents a target of choice for new antivirals development. This complex is required for DNA processing and packaging. pUL52 was shown to be essential for the cleavage of concatemeric HCMV DNA and crucial for viral replication, but its functional domains are not yet identified. Polymorphism analysis was performed by sequencing UL52 from 61 HCMV naive strains and from 14 HCMV strains from patients treated with letermovir. Using sequence alignment and homology modeling, we identified conserved regions and potential functional motifs within the pUL52 sequence. Recombinant viruses were generated with specific serine or alanine substitutions in these putative patterns. Within conserved regions, we identified residues essential for viral replication probably involved in CXXC-like or zinc finger motifs. These results suggest that they are essential for pUL52 structure/function. Thus, these patterns represent potential targets for the development of new antivirals.
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spelling pubmed-84027482021-08-29 New Insights into Human Cytomegalovirus pUL52 Structure Muller, Clotilde Alain, Sophie Gourin, Claire Baumert, Thomas F. Ligat, Gaëtan Hantz, Sébastien Viruses Communication Human cytomegalovirus (HCMV) can cause serious diseases in immunocompromised patients. Current antiviral inhibitors all target the viral DNA polymerase. They have adverse effects, and prolonged treatment can select for drug resistance mutations. Thus, new drugs targeting other stages of replication are an urgent need. The terminase complex (pUL56–pUL89–pUL51) is highly specific, has no counterpart in the human organism, and thus represents a target of choice for new antivirals development. This complex is required for DNA processing and packaging. pUL52 was shown to be essential for the cleavage of concatemeric HCMV DNA and crucial for viral replication, but its functional domains are not yet identified. Polymorphism analysis was performed by sequencing UL52 from 61 HCMV naive strains and from 14 HCMV strains from patients treated with letermovir. Using sequence alignment and homology modeling, we identified conserved regions and potential functional motifs within the pUL52 sequence. Recombinant viruses were generated with specific serine or alanine substitutions in these putative patterns. Within conserved regions, we identified residues essential for viral replication probably involved in CXXC-like or zinc finger motifs. These results suggest that they are essential for pUL52 structure/function. Thus, these patterns represent potential targets for the development of new antivirals. MDPI 2021-08-18 /pmc/articles/PMC8402748/ /pubmed/34452502 http://dx.doi.org/10.3390/v13081638 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Muller, Clotilde
Alain, Sophie
Gourin, Claire
Baumert, Thomas F.
Ligat, Gaëtan
Hantz, Sébastien
New Insights into Human Cytomegalovirus pUL52 Structure
title New Insights into Human Cytomegalovirus pUL52 Structure
title_full New Insights into Human Cytomegalovirus pUL52 Structure
title_fullStr New Insights into Human Cytomegalovirus pUL52 Structure
title_full_unstemmed New Insights into Human Cytomegalovirus pUL52 Structure
title_short New Insights into Human Cytomegalovirus pUL52 Structure
title_sort new insights into human cytomegalovirus pul52 structure
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402748/
https://www.ncbi.nlm.nih.gov/pubmed/34452502
http://dx.doi.org/10.3390/v13081638
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