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Identification of a leucine-zipper motif in pUL51 essential for HCMV replication and potential target for antiviral
Clotilde Muller1, Sophie Alain2, Sébastien Hantz2
1Univ. Limoges, INSERM, CHU Limoges, RESINFIT, U1092, F-87000, Limoges, France.
Abstract:
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.
Insights
New research identifies a leucine zipper domain in human cytomegalovirus (HCMV) protein pUL51, crucial for viral replication. A peptide targeting this domain shows promise as a novel antiviral strategy against HCMV infections.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Human cytomegalovirus (HCMV) poses significant health risks to immunocompromised individuals.
- Current antiviral therapies face limitations due to adverse effects and drug resistance.
- The HCMV terminase complex, including pUL51, is a promising target for new antiviral development.
Purpose of the Study:
- To identify and characterize functional interaction domains within the HCMV pUL51 protein.
- To explore the potential of targeting pUL51 interaction domains for novel antiviral therapies.
- To validate a specific peptide as a potential inhibitor of HCMV replication.
Main Methods:
- Sequence comparison of herpesvirus homologs and protein modeling of pUL51.
- Generation of recombinant HCMV with alanine substitutions to assess domain importance.
- Antiviral assays using a mimetic peptide (TAT-HK29) targeting the pUL51 leucine zipper domain.
- Cytotoxicity evaluation using lactate dehydrogenase (LDH) release assays.
Main Results:
- A Leucine-Zipper (LZ) domain in the C-terminal part of pUL51, involving specific leucine residues (L126, L133, L140, L147), was identified.
- Mutations within this LZ domain significantly impaired viral replication.
- The mimetic peptide TAT-HK29 demonstrated a 27% inhibition of HCMV replication at 1.25 μM without inducing cytotoxicity.
Conclusions:
- The identified leucine zipper domain in pUL51 is critical for HCMV structure and function.
- Targeting protein interaction domains, like the pUL51 LZ domain, is a viable strategy for developing new antiviral agents.
- Mimetic peptides targeting these domains hold therapeutic potential for inhibiting HCMV replication.
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