Dataset Information

Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics

ABSTRACT: Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is a prominent paradigm in drug discovery. In this study, we applied conventional and novel PROTAC approaches to develop broad-spectrum antivirals (targeting key host factors for many different viruses) and virus-specific antivirals (targeting unique viral proteins). With respect to host-directed antivirals, we identified a small molecule degrader, FM-74-103, with pan-antiviral activities, as shown by inhibiting both RNA and DNA viruses. FM-74-103 elicits the selective degradation of human GSPT1, a translation termination factor, which further shuts down translation initiation. With respect to virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). We provided proof-ofprinciple that RNA mimics of viral promoter sequences can be used as molecular glues to recruit viral polymerase (vPOL) and target it for degradation. Collectively, this study shows that TPD can be exploited to rationally design and develop the next generations of antivirals.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung Epithelial Cell Differentiation

DISEASE(S): Covid-19,Influenza

SUBMITTER: Jeffrey Johnson

LAB HEAD: Jeffrey R Johnson

PROVIDER: PXD042352 | Pride | 2023-06-15

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20191010.SwissProt.Hsapiens.fasta	Fasta
	20200911-Uniprot-Influenza-PR8.fasta.fasta	Fasta
	20210626-IM01_Report_new.tsv	Tabular
	20210915_154726_20210914-IM02_Report.tsv	Tabular
	EC20201026-03.raw	Raw

Items per page:

1 - 5 of 76

Similar Datasets

Project description:Classical antiviral therapy inhibit viral proteins and are subject to resistance. To counteract this emergence, alternative strategy has been developed that target cellular factors. We hypothesized that such approach could also be useful to identify broad antivirals. Influenza A virus was used as a model for viral diversity and need for therapy against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to identify a gene-expression signature associated with infection with different influenza A virus subtypes which could help to identify potential antiviral drugs with broad spectrum. Cellular gene expression response to infection with five different human and avian influenza viruses strains was analyzed and 300 genes were determined as differentially expressed between infected and non-infected samples. Strikingly, only a few genes were induced by infection and related to immune response. A more concise list was used to screen connectivity map, a database of drug-associated gene expression profiles, for molecules with inverse profiles than the signature of infection. We hypothesized that such compounds would induce an unfavorable cellular environment for influenza virus replication. Eight potential antivirals including ribavirin were identified, and six inhibited influenza viral growth in vitro. The new pandemic H1N1 virus, which was not used to define the gene expression signature of infection, was inhibited by five of the eight identified molecules, demonstrating that this strategy could help to identify broad spectrum antivirals. This is the first study showing that a gene expression based-screening can be used to identify antivirals. Such approaches could accelerate the drug discovery progress and could be extended to other pathogens. A549 (human lung epithelial cells) were infected with 5 different influenza A strains (A/New Caledonia/20/99 (H1N1), A/Moscow/10/99 (H3N2), A/Lyon/969/09 (H1N1 SOI-V), A/Turkey/582/2006 (H5N1), A/Finch/England/2051/94 (H5N2), and A/Chicken/Italy/2076/99 (H7N1)) or mock infected. Five independant replicates were done and hybridized on a different microarray. The overall design is thus composed of 5 mock samples, and 5x5 infected samples.

Project description:Influenza B virus (IBV) strains are one of the components of seasonal influenza vaccines in both trivalent and quadrivalent formulations. The vast majority of these vaccines are produced in embryonated chickens' eggs. While optimized backbones for vaccine production in eggs exist and are in use for influenza A viruses, no such backbones exist for IBVs, resulting in unpredictable production yields. To generate an optimal vaccine seed virus backbone, we have compiled a panel of 71 IBV strains from 1940 to present day, representing the known temporal and genetic variability of IBV circulating in humans. This panel contains strains from the B/Victoria/2/87-like lineage, B/Yamagata/16/88-like lineage and the ancestral lineage that preceded their split to provide a diverse set that would help to identify a suitable backbone which can be used in combination with hemagglutinin (HA) and neuraminidase (NA) glycoproteins from any IBV strain to be incorporated into the seasonal vaccine. We have characterized and ranked the growth profiles of the 71 IBV strains and the best performing strains were used for co-infection of eggs, followed by serial passaging to select for high-growth reassortant viruses. After serial passaging, we selected 10 clonal isolates based on their growth profiles assessed by hemagglutination and plaque-forming units. We then generated reverse genetics systems for the three clones that performed best in growth curves. The selected backbones were then used to generate different reassortant viruses with HA/NA combinations from high and low titer yielding wild type IBV. When the growth profiles of the recombinant reassortant viruses were tested, the low titer yielding HA/NA viruses with the selected backbones yielded higher titers similar to those from high titer yielding HA/NA combinations. The use of these IBV backbones with improved replication in eggs might increase yields for the influenza B virus components of seasonal influenza virus vaccines.

Dataset Information

Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets