Abstract
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.
Highlights
Human cytomegalovirus (HCMV) is a beta-herpesvirus responsible for significant morbidity and mortality in immunocompromised patients and is the leading cause of congenital viral infection [1]
Sequence alignment in the N-terminal part and in the middle part of pUL52 show a lot of gaps and variability between residues, which is characteristic of a variable region
HCMV is responsible for significant morbidity and mortality in immunocompromised patients and in congenitally infected neonates. pUL52 was shown to be essential for the cleavage of concatemeric HCMV DNA and crucial for viral replication
Summary
Human cytomegalovirus (HCMV) is a beta-herpesvirus responsible for significant morbidity and mortality in immunocompromised patients and is the leading cause of congenital viral infection [1]. The drugs currently approved against HCMV infection are DNA polymerase (pUL54) inhibitors, including ganciclovir and its prodrug, valganciclovir, cidofovir and foscarnet. Despite their efficiency, the limitations of these drugs are their dose-limiting toxicity and resistances emergence leading to therapeutic challenges [2,3,4,5]. New anti-HCMV molecules coming from closer knowledge of novel targets are needed for use instead of, or in combination with, current polymerase pUL54 inhibitors. Resistance mutations were already characterized in vitro and in vivo [7,8,9]
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