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Organization, Function, and Therapeutic Targeting of the Morbillivirus RNA-Dependent RNA Polymerase Complex

View Article: PubMed Central - PubMed

ABSTRACT

The morbillivirus genus comprises major human and animal pathogens, including the highly contagious measles virus. Morbilliviruses feature single stranded negative sense RNA genomes that are wrapped by a plasma membrane-derived lipid envelope. Genomes are encapsidated by the viral nucleocapsid protein forming ribonucleoprotein complexes, and only the encapsidated RNA is transcribed and replicated by the viral RNA-dependent RNA polymerase (RdRp). In this review, we discuss recent breakthroughs towards the structural and functional understanding of the morbillivirus polymerase complex. Considering the clinical burden imposed by members of the morbillivirus genus, the development of novel antiviral therapeutics is urgently needed. The viral polymerase complex presents unique structural and enzymatic properties that can serve as attractive candidates for druggable targets. We evaluate distinct strategies for therapeutic intervention and examine how high-resolution insight into the organization of the polymerase complex may pave the path towards the structure-based design and optimization of next-generation RdRp inhibitors.

No MeSH data available.


Overview of the morbillivirus genus. (A) Phylogenetic analysis of amino acid sequences of nucleocapsid genes of different morbillivirus reference strains. The unrooted tree was constructed using the neighbor-joining method. Branch lengths are relative and proportional to the number of substitutions. The unit of branch length is the number of substitutions (excluding gaps) at each given nucleotide position. Alignments were made with ClustalW2 [2,3,4] and trees rendered with Drawtree from the PHYLIP package 3.67 [5,6]. Genbank accession IDs: FeMV JQ411014; MeV NC_001498; PDV P35944; PPRV NC_006383; CeMV NC_005283; CDV NC_001921; RPV YP_087120.2); (B) Cartoon of morbillivirus genome organization.
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viruses-08-00251-f001: Overview of the morbillivirus genus. (A) Phylogenetic analysis of amino acid sequences of nucleocapsid genes of different morbillivirus reference strains. The unrooted tree was constructed using the neighbor-joining method. Branch lengths are relative and proportional to the number of substitutions. The unit of branch length is the number of substitutions (excluding gaps) at each given nucleotide position. Alignments were made with ClustalW2 [2,3,4] and trees rendered with Drawtree from the PHYLIP package 3.67 [5,6]. Genbank accession IDs: FeMV JQ411014; MeV NC_001498; PDV P35944; PPRV NC_006383; CeMV NC_005283; CDV NC_001921; RPV YP_087120.2); (B) Cartoon of morbillivirus genome organization.

Mentions: The paramyxovirus family encompasses a broad and diverse range of human and animal pathogens. In addition to the morbillivirus genus, the family includes the aquaparamyxo-, avula-, ferla-, henipa-, respiro-, and rubulaviruses. All spread through the respiratory route, but the morbilliviruses are characterized by extremely high infection rates. The genus includes the exclusively human-tropic measles virus (MeV) as well as pathogens infecting terrestrial carnivores (canine distemper virus, CDV), felines (feline morbillivirus, FeMV), livestock (Peste-des-petits-ruminants virus, PPRV, and Rinderpest virus, RPV), or marine mammals (cetacean morbillivirus, CeMV, and phocine distemper virus, PDV) [1] (Figure 1A).


Organization, Function, and Therapeutic Targeting of the Morbillivirus RNA-Dependent RNA Polymerase Complex
Overview of the morbillivirus genus. (A) Phylogenetic analysis of amino acid sequences of nucleocapsid genes of different morbillivirus reference strains. The unrooted tree was constructed using the neighbor-joining method. Branch lengths are relative and proportional to the number of substitutions. The unit of branch length is the number of substitutions (excluding gaps) at each given nucleotide position. Alignments were made with ClustalW2 [2,3,4] and trees rendered with Drawtree from the PHYLIP package 3.67 [5,6]. Genbank accession IDs: FeMV JQ411014; MeV NC_001498; PDV P35944; PPRV NC_006383; CeMV NC_005283; CDV NC_001921; RPV YP_087120.2); (B) Cartoon of morbillivirus genome organization.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5035965&req=5

viruses-08-00251-f001: Overview of the morbillivirus genus. (A) Phylogenetic analysis of amino acid sequences of nucleocapsid genes of different morbillivirus reference strains. The unrooted tree was constructed using the neighbor-joining method. Branch lengths are relative and proportional to the number of substitutions. The unit of branch length is the number of substitutions (excluding gaps) at each given nucleotide position. Alignments were made with ClustalW2 [2,3,4] and trees rendered with Drawtree from the PHYLIP package 3.67 [5,6]. Genbank accession IDs: FeMV JQ411014; MeV NC_001498; PDV P35944; PPRV NC_006383; CeMV NC_005283; CDV NC_001921; RPV YP_087120.2); (B) Cartoon of morbillivirus genome organization.
Mentions: The paramyxovirus family encompasses a broad and diverse range of human and animal pathogens. In addition to the morbillivirus genus, the family includes the aquaparamyxo-, avula-, ferla-, henipa-, respiro-, and rubulaviruses. All spread through the respiratory route, but the morbilliviruses are characterized by extremely high infection rates. The genus includes the exclusively human-tropic measles virus (MeV) as well as pathogens infecting terrestrial carnivores (canine distemper virus, CDV), felines (feline morbillivirus, FeMV), livestock (Peste-des-petits-ruminants virus, PPRV, and Rinderpest virus, RPV), or marine mammals (cetacean morbillivirus, CeMV, and phocine distemper virus, PDV) [1] (Figure 1A).

View Article: PubMed Central - PubMed

ABSTRACT

The morbillivirus genus comprises major human and animal pathogens, including the highly contagious measles virus. Morbilliviruses feature single stranded negative sense RNA genomes that are wrapped by a plasma membrane-derived lipid envelope. Genomes are encapsidated by the viral nucleocapsid protein forming ribonucleoprotein complexes, and only the encapsidated RNA is transcribed and replicated by the viral RNA-dependent RNA polymerase (RdRp). In this review, we discuss recent breakthroughs towards the structural and functional understanding of the morbillivirus polymerase complex. Considering the clinical burden imposed by members of the morbillivirus genus, the development of novel antiviral therapeutics is urgently needed. The viral polymerase complex presents unique structural and enzymatic properties that can serve as attractive candidates for druggable targets. We evaluate distinct strategies for therapeutic intervention and examine how high-resolution insight into the organization of the polymerase complex may pave the path towards the structure-based design and optimization of next-generation RdRp inhibitors.

No MeSH data available.