Identification of a leucine-zipper motif in pUL51 essential for HCMV replication and potential target for antiviral development
Copyright © 2023 Elsevier B.V. All rights reserved..
Human cytomegalovirus (HCMV) can cause serious diseases in immunocompromised patients. Use of current antivirals is limited by their adverse effects and emergence of drug resistance mutations. Thus, new drugs are an urgent need. The terminase complex (pUL56-pUL89-pUL51) represents a target of choice for new antivirals development. pUL51 was shown to be crucial for the cleavage of concatemeric HCMV DNA and viral replication. Its C-terminal part plays a critical role for the terminase complex assembly. However, no interaction domain is clearly identified. Sequence comparison of herpesvirus homologs and protein modelling were performed on pUL51. Importance of a putative interaction domain is validated by the generation of recombinant viruses with specific alanine substitutions of amino acids implicated in the domain. We identified a Leucine-Zipper (LZ) domain involving the leucine residues L126-X6-L133-X6-L140-X6-L147 in C-terminal part of pUL51. These leucines are crucial for viral replication, suggesting the significance for pUL51 structure and function. A mimetic-peptide approach has been used and tested in antiviral assays to validate the interaction domain as a new therapeutic target. Cytotoxicity was evaluated by LDH release measurement. The peptide TAT-HK29, homologous to the pUL51-LZ domain, inhibits HCMV replication by 27% ± 9% at 1.25 μM concentration without cytotoxicity. Our results highlight the importance of a leucine zipper domain in the C-terminal part of pUL51 involving leucines L126, L133, L140 and L147. We also confirm the potential of mimetic peptides to inhibit HCMV replication and the importance to target interaction domains to develop antiviral agents.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:217 |
|---|---|
| Enthalten in: |
Antiviral research - 217(2023) vom: 20. Sept., Seite 105673 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Muller, Clotilde [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antiviral Agents |
|---|
| Anmerkungen: |
Date Completed 30.08.2023 Date Revised 30.08.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.antiviral.2023.105673 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359792502 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359792502 | ||
| 003 | DE-627 | ||
| 005 | 20231226081632.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.antiviral.2023.105673 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1199.xml |
| 035 | |a (DE-627)NLM359792502 | ||
| 035 | |a (NLM)37478917 | ||
| 035 | |a (PII)S0166-3542(23)00151-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Muller, Clotilde |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of a leucine-zipper motif in pUL51 essential for HCMV replication and potential target for antiviral development |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.08.2023 | ||
| 500 | |a Date Revised 30.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier B.V. All rights reserved. | ||
| 520 | |a Human cytomegalovirus (HCMV) can cause serious diseases in immunocompromised patients. Use of current antivirals is limited by their adverse effects and emergence of drug resistance mutations. Thus, new drugs are an urgent need. The terminase complex (pUL56-pUL89-pUL51) represents a target of choice for new antivirals development. pUL51 was shown to be crucial for the cleavage of concatemeric HCMV DNA and viral replication. Its C-terminal part plays a critical role for the terminase complex assembly. However, no interaction domain is clearly identified. Sequence comparison of herpesvirus homologs and protein modelling were performed on pUL51. Importance of a putative interaction domain is validated by the generation of recombinant viruses with specific alanine substitutions of amino acids implicated in the domain. We identified a Leucine-Zipper (LZ) domain involving the leucine residues L126-X6-L133-X6-L140-X6-L147 in C-terminal part of pUL51. These leucines are crucial for viral replication, suggesting the significance for pUL51 structure and function. A mimetic-peptide approach has been used and tested in antiviral assays to validate the interaction domain as a new therapeutic target. Cytotoxicity was evaluated by LDH release measurement. The peptide TAT-HK29, homologous to the pUL51-LZ domain, inhibits HCMV replication by 27% ± 9% at 1.25 μM concentration without cytotoxicity. Our results highlight the importance of a leucine zipper domain in the C-terminal part of pUL51 involving leucines L126, L133, L140 and L147. We also confirm the potential of mimetic peptides to inhibit HCMV replication and the importance to target interaction domains to develop antiviral agents | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HCMV | |
| 650 | 4 | |a Leucine-zipper | |
| 650 | 4 | |a Mimetic-peptides | |
| 650 | 4 | |a Terminase | |
| 650 | 4 | |a pUL51 | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Viral Proteins |2 NLM | |
| 650 | 7 | |a Endodeoxyribonucleases |2 NLM | |
| 650 | 7 | |a EC 3.1.- |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 700 | 1 | |a Alain, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a Hantz, Sébastien |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Antiviral research |d 1983 |g 217(2023) vom: 20. Sept., Seite 105673 |w (DE-627)NLM012601756 |x 1872-9096 |7 nnns |
| 773 | 1 | 8 | |g volume:217 |g year:2023 |g day:20 |g month:09 |g pages:105673 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.antiviral.2023.105673 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 217 |j 2023 |b 20 |c 09 |h 105673 | ||