Potential new therapeutic targets: pUL77 and pUL93, partner proteins of HCMV packaging complex - Pharmacologie et Transplantation Access content directly
Conference Poster Year : 2024

Potential new therapeutic targets: pUL77 and pUL93, partner proteins of HCMV packaging complex

Abstract

Introduction and objectives: Cytomegalovirus is the leading cause of congenital viral infection, responsible for high morbidity in transplant recipients. Letermovir is an antiviral agent targeting the CMVH packaging complex composed of the pUL56, pUL89 and pUL51 proteins. The complex's partner proteins, pUL77 and pUL93, have been shown to play an indispensable role in encapsidation. However, little is known about their precise functions and whether they may be linked to the mode of action of letermovir. The aim of this study is therefore to define their structure-function relationships. Materials and methods: Identification of conserved regions was achieved by ClustalW alignment of 18 sequences of pUL77 and pUL93 homologs from different herpesviruses with strain AD169. The UL77 and UL93 genes of 5 reference CMVH strains, 30 strains naïve to any letermovir treatment and 13 strains from patients treated with LTM were sequenced by SANGER or NGS. 45 sequences from Genbank naïve strains completed the results obtained. Amino acid mutations were listed in the form of two binary heatmaps. 3D modeling was performed using the I-TASSER and ALPHAFOLD servers. The mutations selected under letermovir were studied in recombinant virus. Results, discussion and conclusion: Four conserved domains were identified in pUL77 and three in pUL93. Two novel mutations were identified in each protein in letermovir-treated patients, suggesting a possible interaction of these proteins with letermovir. Modeling of these two proteins revealed domains such as a coiled-coil motif in the first hundred amino acids of pUL77. Antiviral and replicative assays were carried out to determine the impact of these new mutations. A study on recombinant viruses is also planned to confirm the presence of the putative NLSs described in the literature for each of the two proteins.
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Dates and versions

hal-04594184 , version 1 (30-05-2024)

Identifiers

  • HAL Id : hal-04594184 , version 1

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Claire Gourin, Florent Di Meo, Sophie Alain, Sébastien Hantz. Potential new therapeutic targets: pUL77 and pUL93, partner proteins of HCMV packaging complex. Microbiology Day - 5th edition, May 2024, Talence (33), France. , 2024. ⟨hal-04594184⟩
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