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Brd2 inhibitor ABBV-744 inhibits SARS-CoV-2 infection in Syrian Hamsters

ABSTRACT: Brd2 inhibitor ABBV-744 inhibits SARS-CoV-2 infection in Syrian Hamsters

PROVIDER: PRJNA758692 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15663700.fastq.gz	Fastqsanger.gz
	SRR15663701.fastq.gz	Fastqsanger.gz
	SRR15663702.fastq.gz	Fastqsanger.gz
	SRR15663703.fastq.gz	Fastqsanger.gz
	SRR15663704.fastq.gz	Fastqsanger.gz

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Brd2 inhibitor ABBV-744 inhibits SARS-CoV-2 infection in Syrian Hamsters

Project description:We tested if Brd2 inhibitor ABBV-744 could reduce SARS-CoV-2 infection in Syrian Hamsters. Three days post-infection, the lungs of hamsters were harvested and subjected to RNA-seq. Infected, but untreated, hamsters showed marked up-regulation of a number of genes including ISGs when compared to uninfected controls. In contrast, hamsters treated with ABBV-744 showed a down-regulation of ISG levels, confirming ABBV-744 activity. Thus, Brd2 inhibition can decrease SARS-CoV-2 infection in Syrian Hamsters.

2021-09-02 | GSE182994 | GEO

Changes in the gene expression in the inferior colliculus of the sound stimulated both control Syrian hamsters and the strain GASH:Sal.

Project description:Using microarray analyses and subsequent verification by RT-PCR, we studied the changes in gene expression in the inferior colliculus after an ictal event in one models of audiogenic epilepsy, genetic audiogenic seizure hamster (GASH:Sal). GASH:Sal, a hamster strain developed at the University of Salamanca, exhibits genetic audiogenic epilepsy similar to human Grand Mal epilepsy. GASH:Sal shows an autosomal recessive inheritance for susceptibility to audiogenic seizures, which manifest more severely in young animals; the seizure severity progressively declines with age. Genetic animal models of epilepsy are an important tool for further understanding the basic cellular mechanisms underlying epileptogenesis and for developing novel antiepileptic drugs. We conducted a comparative study of gene expression in the inferior colliculus, a nucleus that triggers audiogenic seizures, using two animal models, the Wistar audiogenic rat (WAR) and the genetic audiogenic seizure hamster (GASH:Sal). For this purpose, both models were subjected to auditory stimulation, and 60 minutes after stimulation, the inferior colliculi were collected. As a control, intact Wistar rats and Syrian hamsters were subjected to identical stimulation and tissue preparation protocols to those performed on the experimental animals. A total of 24 animals were used in this study according to the following distribution: 12 control Syrian hamsters (Mesocricetus auratus) and 12 GASH:Sal at 16 weeks of age and a body weight of approximately 60 g. Six animals Syrian and GASH:Sal hamsters, respectively, were exposed to auditory stimulation, and 60 min after the seizures, we harvested the IC for all gene expression analyses (stimulated Syrian hamsters and stimulated GASH:Sal hamsters). As controls, other six animals Syrian and GASH:Sal hamsters, respectively, were not exposed to the same stimulation (Syrian hamsters and GASH:Sal hamsters).

2015-12-31 | E-GEOD-74043 | biostudies-arrayexpress

BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2

Project description:We performed RNA sequencing of Calu-3 cells after treatment with the BET-domain inhibitors JQ-1 and ABBV-744 as well as BRD2 CRISPRi knockdown. We also included CRISPRi knockdown of two other validated hit genes from our screen, COMP and ACE2.

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Duper is a Cryptochrome 1 null mutation in Syrian hamsters

Project description:The duper mutation is a recessive mutation that shortens the period length of the circadian rhythm in Syrian hamsters. These animals show a large phase shift when responding to light pulses. Using two distinct ecotypes and a fast homozygosity mapping strategy, we identified duper as an early nonsense allele of Cryptochrome 1 (Cry1) leading to a short, unstable protein.

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Mesocricetus auratus breed:Golden Syrian hamsters

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A Single Intranasal Vaccination with a Rationally Attenuated SARS-CoV-2 Elicits Strong Humoral Immune Response and Is Protective in Syrian Hamsters

Project description:Very few live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are currently in pre-clinical or clinical development. We rationally attenuated SARS-CoV-2 (isolate WA1/2020) by removing the polybasic cleavage site within the spike protein and the open reading frames (ORFs) 6-8, and by introducing a pair of mutations into the non-structural protein 1 (Nsp1). The derived virus (WA1-DPRRA-ORF6-8-Nsp1K164A/H165A) became severely attenuated in both the K18-human ACE2 (hACE2) transgenic mice and in Syrian hamsters. Transcriptomic profiling of nasal turbinates and lung tissues of infected Syrian hamsters confirmed that WA1-DPRRA-ORF6-8-Nsp1K164A/H165A attenuated the upregulation of proinflammatory pathways. A single intranasal immunization of just 100 PFU of the WA1-DPRRA-ORF6-8-Nsp1K164A/H165A elicited binding and neutralizing antibody responses in Syrian hamsters and completely protected against SARS-CoV-2-induced weight loss and pneumonia. These data demonstrate the feasibility of rational attenuation of SARS-CoV-2. WA1-DPRRA-ORF6-8-Nsp1K164A/H165A represents a promising live attenuated vaccine candidate.

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Selective inhibition of the second bromodomain of BET family proteins results in robust antitumor activity in preclinical models of acute myeloid leukemia

Project description:Dual bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4 and BRDt only displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of GI toxicity, have presented as dose limiting adverse events that may prevented escalation to higher dose levels for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain (BD2) of the four BET family proteins. In contrast to the broad antiproliferative activities observed with DbBi, ABBV-744 displayed significant antiproliferative activities largely but not exclusively in cancer cell lines derived from AML and androgen receptor (AR) positive prostate cancer. Studies in AML xenograft models demonstrated anti-tumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with improved tolerability. Enhanced anti-tumor efficacy was also observed with the combination of ABBV-744 and the Bcl-2 inhibitor, venetoclax (ABT-199) compared to monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).

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Innate and adaptive immune responses to SARS-CoV-2 in Syrian hamsters disclosed by single-cell sequencing and high-throughput proteomics

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