Abstract
The paramyxovirus family includes major human and animal pathogens, including measles virus, mumps virus, and human respiratory syncytial virus (RSV), as well as the emerging zoonotic Hendra and Nipah viruses. In the U.S., RSV is the leading cause of infant hospitalizations due to viral infectious disease. Despite their clinical significance, effective drugs for the improved management of paramyxovirus disease are lacking. The development of novel anti-paramyxovirus therapeutics is therefore urgently needed. Paramyxoviruses contain RNA genomes of negative polarity, necessitating a virus-encoded RNA-dependent RNA polymerase (RdRp) complex for replication and transcription. Since an equivalent enzymatic activity is absent in host cells, the RdRp complex represents an attractive druggable target, although structure-guided drug development campaigns are hampered by the lack of high-resolution RdRp crystal structures. Here, we review the current structural and functional insight into the paramyxovirus polymerase complex in conjunction with an evaluation of the mechanism of activity and developmental status of available experimental RdRp inhibitors. Our assessment spotlights the importance of the RdRp complex as a premier target for therapeutic intervention and examines how high-resolution insight into the organization of the complex will pave the path toward the structure-guided design and optimization of much-needed next-generation paramyxovirus RdRp blockers.
Highlights
Paramyxoviruses are enveloped, non-segmented and single-stranded RNA viruses with negative genome polarity (NNRV) in the order Mononegavirales, which includes the Bornaviridae, Filoviridae, and Rhabdoviridae families
Nucleoside analogs contain non-canonical bases that act as chain terminators after intracellular phosphorylation to the corresponding nucleotide and incorporation into the nascent chain (De Clercq and Neyts, 2009; Soriano et al, 2013) While nucleoside analogs have shown extreme clinical success, ribavirin is currently the only substrate analog licensed against a paramyxovirus disease, the treatment of respiratory syncytial virus (RSV) infection
The high contagiousness of paramyxoviruses, the lack of vaccine protection against several clinically highly significant members of the family, and the deliberate decline of vaccination against other family members due to religious believes or concerns about vaccine safety create an urgent need for the development of efficacious paramyxovirus therapeutics
Summary
Paramyxoviruses are enveloped, non-segmented and single-stranded RNA viruses with negative genome polarity (NNRV) in the order Mononegavirales, which includes the Bornaviridae, Filoviridae, and Rhabdoviridae families. The paramyxoviruses encompass major human and animal pathogens such as respiratory syncytial virus (RSV), measles virus (MeV), mumps virus (MuV), and Newcastle disease virus (NDV). Among hospitalized RSV-infected children less than 2 years of age, viral load on day three of hospitalization was associated with a requirement for intensive care and respiratory failure (El Saleeby et al, 2011). These findings spotlight a window of opportunity for improved RSV disease management through therapeutics, but post-exposure prophylaxis may be the only viable indication against other clinically significant members of the family. Functional studies on N, P, and L have confirmed that each of the RdRp components can individually and differentially affect the processes of mRNA synthesis and genome replication (Perlman and Huang, 1973; Chen et al, 1997; Fearns et al, 1997; Hwang et al, 1999; Galloway and Wertz, 2008, 2009; Harouaka and Wertz, 2009)
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