Abstract
The human cytomegalovirus (HCMV) terminase complex consists of several components acting together to cleave viral DNA into unit length genomes and translocate them into capsids, a critical process in the production of infectious virions subsequent to DNA replication. Previous studies suggest that the carboxyl-terminal portion of the pUL56 subunit interacts with the pUL89 subunit. However, the specific interacting residues of pUL56 remain unknown. We identified a conserved sequence in the C-terminal moiety of pUL56 (671WMVVKYMGFF680). Overrepresentation of conserved aromatic amino acids through 20 herpesviruses homologues of pUL56 suggests an involvement of this short peptide into the interaction between the larger pUL56 terminase subunit and the smaller pUL89 subunit. Use of Alpha technology highlighted an interaction between pUL56 and pUL89 driven through the peptide 671WMVVKYMGFF680. A deletion of these residues blocks viral replication. We hypothesize that it is the consequence of the disruption of the pUL56-pUL89 interaction. These results show that this motif is essential for HCMV replication and could be a target for development of new small antiviral drugs or peptidomimetics.
Highlights
Human cytomegalovirus (HCMV), a beta herpesvirus, can cause serious diseases in immunocompromised patients
The terminase complex is highly specific for human cytomegalovirus (HCMV), has no counterpart in the human organism, and represents a target of choice for new antivirals development
Terminase subunits are proteins forming a hetero-oligomeric complex involved in this process
Summary
Human cytomegalovirus (HCMV), a beta herpesvirus, can cause serious diseases in immunocompromised patients. The terminase complex is highly specific for HCMV, has no counterpart in the human organism, and represents a target of choice for new antivirals development. This has been confirmed by the recent development of letermovir in the transplant setting[3, 4]. BAC mutagenesis and Alpha technology using purified proteins subsequently validated that the aromatic rich peptide 671WMVVKYMGFF680 pUL56(671-680) in the C-terminal of pUL56 is involved in interaction with pUL89. These results could contribute for development of new antiviral drugs, peptides or antibodies against HCMV
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