Target Discovery for Host-Directed Antiviral Therapies: Application of Proteomics Approaches

Çakır, Merve; Obernier, Kirsten; Forget, Antoine; Krogan, Nevan J.

doi:10.1128/msystems.00388-21

Cited by 21 publications

(11 citation statements)

References 127 publications

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“…COVID-19 has accentuated the need for drug discovery, and this has helped propel the need for a better understanding of virus–host cell interactions, with the hope that this could facilitate drug breakthroughs [ 41 ]. Antiviral drugs can target the virus directly, or the cellular components that are used for viral replication.…”

Section: The Virus–host Cell Interface For Viral Replicationmentioning

confidence: 99%

Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication

Tripp

Martin²

2022

Viruses

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Viral replication and transmissibility are the principal causes of endemic and pandemic disease threats. There remains a need for broad-spectrum antiviral agents. The most common respiratory viruses are endemic agents such as coronaviruses, respiratory syncytial viruses, and influenza viruses. Although vaccines are available for SARS-CoV-2 and some influenza viruses, there is a paucity of effective antiviral drugs, while for RSV there is no vaccine available, and therapeutic treatments are very limited. We have previously shown that probenecid is safe and effective in limiting influenza A virus replication and SARS-CoV-2 replication, along with strong evidence showing inhibition of RSV replication in vitro and in vivo. This review article will describe the antiviral activity profile of probenecid against these three viruses.

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Section: The Virus–host Cell Interface For Viral Replicationmentioning

confidence: 99%

Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication

Tripp

Martin²

2022

Viruses

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“…The successful development of antiviral therapies requires the detailed knowledge of viral protein function or of host factors that support virus replication [25]. RVFV enters cells by receptor-mediated endocytosis and releases its nucleocapsid after fusion of virus-endosomal membranes.…”

Section: Introductionmentioning

confidence: 99%

Identification of host factors for Rift Valley Fever Phlebovirus

Balaraman,

Indran,

et al. 2023

Preprint

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BackgroundRift Valley fever phlebovirus (RVFV) is a zoonotic pathogen that causes Rift Valley fever (RVF) in livestock and humans. Currently, there is no licensed human vaccine or antiviral drug to control RVF. Although multiple species of animals and humans are vulnerable to RVFV infection, host factors affecting susceptibility are not well understood.MethodologyTo identify the host factors or genes essential for RVFV replication, we conducted a CRISPR-Cas9 knock-out screen in human A549 cells. We then validated the putative genes using siRNA-mediated knockdowns and CRISPR-Cas9-mediated knockout studies, respectively. The role of a candidate gene in the virus replication cycle was assessed by measuring intracellular viral RNA accumulation, and the virus titers by plaque assay or TCID50assay.FindingsWe identified approximately 900 genes with potential involvement in RVFV infection and replication. Further evaluation of the effect of six genes on viral replication using siRNA-mediated knockdowns found that silencing two genes (WDR7 and LRP1) significantly impaired RVFV replication. For further analysis, we focused on theWDR7gene since the role ofLRP1in RVFV replication was previously described in detail. Knock-out A549 cell lines were generated and used to dissect the effect ofWRD7on RVFV and another bunyavirus, La Crosse encephalitis virus (LACV). We observed significant effects ofWDR7knock-out cells on both intracellular RVFV RNA levels and viral titers. At the intracellular RNA level,WRD7affected RVFV replication at a later phase of its replication cycle (24h) when compared to LACV which was affected an earlier replication phase (12h).ConclusionIn summary, we have identifiedWDR7as an essential host factor for the replication of two relevant bunyaviruses, RVFV and LACV. Future studies will investigate the mechanistic role by whichWDR7facilitates Phlebovirus replication.Authors SummaryRift Valley fever phlebovirus is a high consequence pathogen that infects multiple animal species and also humans. Currently, there are no control measures available to treat RVF in humans and to prevent the incursion of Rift Valley fever virus into non-endemic countries. RVFV poses a significant threat to animal and human health in countries where it is endemic. RVFV replication depends on the host’s machinery to complete its replication cycle. Therefore, one way to control virus replication is to disrupt the interaction between the virus and the host proteins important for replication. In this study, we identified a host factor, the WDR7 gene, that is critical for RVFV replication. The identification of this host factor is important as it can potentially lead to the development of antiviral strategies to control Rift Valley fever in both humans and animals.

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“…In the last decades, protein-protein interaction (PPI) discovery experiments have gained momentum among the different approaches to study viral diseases ( de Chassey et al, 2014 ; Goodacre et al, 2020 ). Indeed, the systematic mapping of interactions between viral and host proteins can provide a better understanding of the molecular mechanisms of viral infections and identify viral perturbations underlying disease phenotypes, thus suggesting novel potential targets of therapeutic intervention ( Cakir et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Intricacy of the Viral-Human Protein Interaction Networks: Resources, Data, and Analyses

et al. 2022

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Viral infections are one of the major causes of human diseases that cause yearly millions of deaths and seriously threaten global health, as we have experienced with the COVID-19 pandemic. Numerous approaches have been adopted to understand viral diseases and develop pharmacological treatments. Among them, the study of virus-host protein-protein interactions is a powerful strategy to comprehend the molecular mechanisms employed by the virus to infect the host cells and to interact with their components. Experimental protein-protein interactions described in the scientific literature have been systematically captured into several molecular interaction databases. These data are organized in structured formats and can be easily downloaded by users to perform further bioinformatic and network studies. Network analysis of available virus-host interactomes allow us to understand how the host interactome is perturbed upon viral infection and what are the key host proteins targeted by the virus and the main cellular pathways that are subverted. In this review, we give an overview of publicly available viral-human protein-protein interactions resources and the community standards, curation rules and adopted ontologies. A description of the main virus-human interactome available is provided, together with the main network analyses that have been performed. We finally discuss the main limitations and future challenges to assess the quality and reliability of protein-protein interaction datasets and resources.

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Target Discovery for Host-Directed Antiviral Therapies: Application of Proteomics Approaches

Cited by 21 publications

References 127 publications

Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication

Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication

Identification of host factors for Rift Valley Fever Phlebovirus

The Intricacy of the Viral-Human Protein Interaction Networks: Resources, Data, and Analyses

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