An inability to maintain the ribonucleoprotein genomic structure is responsible for host detection of negative-sense RNA viruses

Abstract

Defective viral genomes and viral antagonists are key determinants of the host antiviral responseThe host response and defective viral genome generation further exasperate NP availability NP is an optimal drug target for the whole phylum of negative-sense RNA viruses SUMMARY Cellular biology has a uniformity not shared amongst viruses. This is perhaps best exemplified by negative-sense RNA viruses that encode their genetic material as a ribonucleoprotein complex composed of genome, RNA-dependent RNA polymerase, and the nucleoprotein. Here we demonstrate that limiting nucleoprotein availability not only universally culminates in a replicative catastrophe for negative-sense RNA viruses, but it results in the production of aberrant genomic material and induction of the interferonbased host defenses. This dynamic illustrates the tremendous stress imposed on negative-sense RNA viruses during replication as genomic products accumulate in an environment that requires an increasing demand on nucleoprotein availability. We show that limiting NP by RNA interference or drug targeting blocks replication and primes neighboring cells through the production of interferon. Together, these results demonstrate that the nucleoprotein represents the Achilles heel of the entire phylum of negative-sense RNA viruses. Here we establish this principle for a diverse collection of human pathogens and propose that the nucleoprotein should be a primary target for the development of future antiviral drugs. Manuscript

Targeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders

“… 10 − 12 The structural elements within these regions could be novel targets for small molecule intervention. 13 Indeed, targeting functional structural elements within disease-associated RNAs affords bioactive small molecules, 14 , 15 including those within RNAs of viral origin such as SARS-CoV 16 , 17 and SARS-CoV-2. 18 …”

“…10−12 The structural elements within these regions could be novel targets for small molecule intervention. 13 Indeed, targeting functional structural elements within disease-associated RNAs affords bioactive small molecules, 14,15 including those within RNAs of viral origin such as SARS-CoV 16,17 and SARS-CoV-2. 18 Of particular interest, sites of structural convergence were identified within the SARS-CoV-2 frameshifting element (FSE), which controls translation of the pp1a and pp1ab polyproteins that are critical for viral replication and pathogenesis (Figure 1A).…”

“…Several groups have interrogated the structure of the SARS-CoV-2 RNA genome computationally and experimentally, identifying a convergence of structures in both coding and noncoding regions. − The structural elements within these regions could be novel targets for small molecule intervention . Indeed, targeting functional structural elements within disease-associated RNAs affords bioactive small molecules, , including those within RNAs of viral origin such as SARS-CoV , and SARS-CoV-2 …”

Comparative Multiplexed Interactomics of SARS-CoV-2 and Homologous Coronavirus Nonstructural Proteins Identifies Unique and Shared Host-Cell Dependencies

“…4 CoV strains also engage a variety of host immune processes in infected cells. Pathogenic strains more strongly interfere with interferon I signaling 4,5 and induce apoptosis and pyroptosis. 6−9 Ensembles of virus-host protein−protein interactions (PPIs) orchestrate the reprogramming of these processes during infection.…”

Viral fossils in marsupial genomes: secret cellular guardians

“…One theory suggests the nucleocapsid and polymerase proteins are prime targets for negative sense ssRNA viruses 11 . In these viruses, the nucleocapsid encapsulates the other viral proteins, and any degradation of this protein will lead to the exposure of pathogenassociated molecular patterns (PAMPs) and inhibition of viral replication 12 . Following this, it would make sense that these EVEs from these two viral genes are retained in host chromosomes to act as an effective antiviral defence against invasion from similar negative sense RNA viruses.…”