Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells
AuthorsPickard, Adam; orcid: 0000-0001-9757-143X; email: email@example.com
Calverley, Ben C.; orcid: 0000-0001-9403-0363
Chang, Joan; orcid: 0000-0002-7283-9759
Garva, Richa; orcid: 0000-0001-7752-8936
Kadler, Karl E.; orcid: 0000-0003-4977-4683; email: firstname.lastname@example.org
MetadataShow full item record
AbstractCOVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, therapeutics that can help manage the disease are still required until immunity has been achieved globally. The identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2-ΔOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in-line with reported proteinuria and liver damage in patients with COVID-19. Using the nano-luciferase as a measure of virus replication we identified 35 drugs that reduced replication in Vero cells and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.
CitationPLOS Pathogens, volume 17, issue 9, page e1009840
PublisherPublic Library of Science
DescriptionFrom PLOS via Jisc Publications Router
History: received 2021-05-27, accepted 2021-07-26, collection 2021-09, epub 2021-09-09
Publication status: Published
Funder: wellcome (london); Grant(s): 110126/Z/15/Z
Funder: Wellcome (London); Grant(s): 203128/Z/16/Z
Funder: NIHR Manchester Research Centre
Funder: Fungal Infection Trust
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No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database StudyDominguez-Valentin, Mev; orcid: 0000-0001-7856-0057; email: Mev.Dominguez.Valentin@rr-research.no; Plazzer, John-Paul; orcid: 0000-0001-5114-4301; email: email@example.com; Sampson, Julian R.; email: Sampson@cardiff.ac.uk; Engel, Christoph; orcid: 0000-0002-7247-282X; email: firstname.lastname@example.org; Aretz, Stefan; orcid: 0000-0002-5228-1890; email: email@example.com; Jenkins, Mark A.; email: firstname.lastname@example.org; Sunde, Lone; email: email@example.com; Bernstein, Inge; email: firstname.lastname@example.org; Capella, Gabriel; orcid: 0000-0002-4669-7320; email: email@example.com; Balaguer, Francesc; orcid: 0000-0002-0206-0539; email: firstname.lastname@example.org; et al. (MDPI, 2021-06-28)Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.Eales, James M; orcid: 0000-0001-6238-5952; Jiang, Xiao; orcid: 0000-0002-1442-8927; Xu, Xiaoguang; orcid: 0000-0003-4568-1623; Saluja, Sushant; Akbarov, Artur; Cano-Gamez, Eddie; McNulty, Michelle T; Finan, Christopher; orcid: 0000-0002-3319-1937; Guo, Hui; orcid: 0000-0003-0282-6933; Wystrychowski, Wojciech; et al. (2021-05-06)The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?Park, JooYong; email: email@example.com; Choi, Ji-Yeob; email: firstname.lastname@example.org; Choi, Jaesung; email: email@example.com; Chung, Seokang; email: firstname.lastname@example.org; Song, Nan; orcid: 0000-0002-9182-1060; email: email@example.com; Park, Sue K.; orcid: 0000-0001-5002-9707; email: firstname.lastname@example.org; Han, Wonshik; email: email@example.com; Noh, Dong-Young; email: firstname.lastname@example.org; Ahn, Sei-Hyun; email: email@example.com; Lee, Jong Won; email: firstname.lastname@example.org; et al. (MDPI, 2021-05-14)In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.