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

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.

Efficient isolation on Vero.DogSLAMtag cells and full genome characterization of Dolphin Morbillivirus (DMV) by next generation sequencing

“…Indeed, they form a separate clade for each gene. This seems to confirm that homologous recombination is an uncommon event in Morbillivirus and, in general, in non-segmented negative stranded RNA viruses 17 , 18 . However, Park et al .…”

“…The L protein, together with the phospho- (P) protein is encapsidated into a ribonucleoprotein complex (RNP) formed by the nucleocapsid (N) protein 12 . In the morbillivirus genus, the L protein harbors all enzymatic activities necessary for RNA transcription and replication 17 . From a GenBank search for CeMV sequences at the moment of writing, the only L gene sequence publicly available can be retrieved from the reference sequence of the complete 1990 DMV genome (excluding the two Spanish sequences of our phylogenetic analysis that include only a very short region corresponding to the first 10 amino acids of the L protein).…”

Structure and organization of paramyxovirus particles

“…While Ntail is structurally intrinsically disordered, areas of high sequence conservation were identified that engage in multiple protein-protein interactions [69]. A molecular recognition element (MoRE) mediates transient binding of the P-L polymerase complex [70], and the terminal residues of the Ntail were demonstrated to mediate specific contacts with the MeV M protein [71], promoting genome packaging into nascent virions.…”

Masern – Warum ist die Impfung notwendig und wie gehe ich mit Impfgegnern um?

“…2 × 10 5 in dieser Altersgruppe wird dennoch wegen eines möglichen Vitamin-A-Man-gels empfohlen [52]. Symptomatisch mit Vitamin A sollten vor allem pädiatrische Patienten während der asymptomatischen Expositionsphase, also vor dem klinischen Ausbruch der Infektion, behandelt werden [53].…”