Computational modeling identifies drug candidates for SARS-CoV-2

Scientists from the Division of the National Toxicology Program and their collaborators used computational modeling to probe databases and identify existing drugs that could be repurposed to fight SARS-CoV-2, the virus that causes COVID-19.

Proteases are enzymes that break down proteins. An essential step in the formation of infectious viral particles is the breakdown of precursor viral proteins by viral proteases. Protease inhibitors, a class of antiviral drugs, block the activity of viral proteases. The main protease (Mpro) of SARS-CoV-2 is a proposed target for COVID-19 drugs. The structure and activity of Mpro is highly conserved across the coronavirus family. In this study, previous data on drug interactions with SARS-CoV Mpro was used to develop quantitative structure-activity relationship (QSAR) models, which the team used to virtually screen all drugs in the DrugBank database. They identified 42 drugs that could be repurposed against SARS-CoV-2 Mpro.

Following this discovery, the National Center for Advancing Translational Science (NCATS) released experimental data on the activity of approved clinical drugs against SARS-CoV-2 Mpro. NCATS tested 11 of the 42 drugs identified computationally and 3 showed activity against SARS-CoV-2 Mpro. The work verified the QSAR models’ ability to identify drugs active against SARS-CoV-2. (VP)

Citation: Alves VM, Bobrowski T, Melo-Filho CC, Korn D, Auerbach S, Schmitt C, Muratov EN, Tropsha A. 2020. QSAR modeling of SARS-CoV Mpro inhibitors identifies sufugolix, cenicriviroc, proglumetacin, and other drugs as candidates for repurposing against SARS-CoV-2. Mol Inform; doi:10.1002/minf.202000113 [Online 28 July 2020].

Maternal fatty acids level associated with newborn size

NIEHS scientists and their collaborators report that polyunsaturated fatty acids and their metabolic derivatives called eicosanoids in pregnant women are associated with infant size at delivery. This work also provides a novel longitudinal characterization of eicosanoids in blood plasma during different gestational ages of pregnancy. The results link inflammatory eicosanoids with adverse fetal growth outcomes.

The blood plasma concentration of polyunsaturated fatty acids, including omega-3 and omega-6, in study participants were found to be higher in cases of small birth weight and lower in cases of large birth weight. Small and large birth weights were defined as equal to or less than 10th and equal to or greater than 90th percentile for gestational age, respectively. In addition, certain eicosanoids, which are known to derive from inflammatory processes from these fatty acids, were found to be exclusively higher in pregnancy cases resulting in small birth weight.

These findings indicate that dysregulation of inflammatory pathways during pregnancy could lead to abnormal fetal development. The study provides new insights into the types of fatty acids and eicosanoids that are associated with such abnormalities. (PR)

Citation: Welch BM, Keil AP, van't Erve TJ, Deterding LJ, Williams JG, Lih FB, Cantonwine DE, McElrath TF, Ferguson KK. 2020. Longitudinal profiles of plasma eicosanoids during pregnancy and size for gestational age at delivery: A nested case-control study. PLoS Med 17(8):e1003271.

HNF4alpha dictates liver cancer response to methionine restriction

NIEHS scientists and collaborators discovered that hepatocyte nuclear factor four alpha (HNF4alpha) and sulfur amino acid (SAA) metabolism determines whether methionine restriction reduces liver cancer growth. Previous research showed that limiting dietary intake of methionine inhibits cancer proliferation in several cancer cell lines. The goal of this study was to determine the precise molecular mechanisms involved in how different cancer cells respond to methionine restriction.

HNF4alpha is critically important in maintaining healthy liver cells, and its levels drop in liver cancer cells. Loss of HNF4alpha leads to the transformation of differentiated cells into undifferentiated cells called mesenchymal cells, which promote cancer. The team showed that HNF4alpha transcriptionally regulated SAA metabolism. They also demonstrated that knocking down HNF4alpha or SAA enzymes in HNF4alpha-positive epithelial liver cancer lines reduced sensitivity to methionine restriction or the cancer drug sorafenib. These knock downs facilitated the epithelial-mesenchymal transition and activated cell migration, both of which are necessary for metastasis. In short, the researchers determined what controlled the response of liver cancers to methionine limitation and generated a highly applicable biomarker for the treatment of liver cancers. (NA)

Citation: Xu Q, Li Y, Gao X, Kang K, Williams JG, Tong L, Liu J, Ji M, Deterding LJ, Tong X, Locasale JW, Li L, Shats I, Li X. 2020. HNF4alpha regulated sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer. Nat Commun 11(1):3978. (Story)

High-fat diet rewires brain, encourages fatty food consumption

Researchers at NIEHS and collaborators at the National Institute of Diabetes and Digestive and Kidney Diseases uncovered the neural basis behind the drive to select calorie-rich foods over nutritionally balanced diets. The findings partly explain the difficulty of dieting.

One group of mice received a standard diet (SD) consisting of regular chow, and another group ate a high-fat diet (HFD). When the HFD mice were switched to SD, they refused to eat. Even after fasting to stimulate their appetites, HFD mice preferred fatty food, rather than regular chow. Research from other groups found that a dense cluster of agouti-related peptide (AgRP) producing neurons located in the hypothalamic arcuate nucleus (ARC) of the brain are responsible for the unpleasant sensations associated with hunger and the motivating drive to eat.

Using a fluorescent calcium sensor to detect altered responses in ARCAgRP neurons, the researchers observed a strong disconnect between signals of hunger versus satiety and actual caloric content. Searching for food, also known as food discovery, typically dulls this signal. However, for HFD mice that were switched to SD, regular chow was no longer able to fully alleviate the response. The authors also saw that dopamine signaling, which is responsible for the pleasurable feelings from eating, were significantly diminished in SD following HFD exposure. (SM)

Citation: Mazzone CM, Liang-Guallpa J, Li C, Wolcott NS, Boone MH, Southern M, Kobzar NP, Salgado IA, Reddy DM, Sun F, Zhang Y, Li Y, Cui G, Krashes MJ. 2020. High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nat Neurosci 23(10):1253–1266.

H/ACA snoRNA regulated during stem cell differentiation

H/ACA small nucleolar RNAs (snoRNAs) are cell-type specific and a subset are specifically regulated during differentiation, according to NIEHS researchers. H/ACA snoRNAs guide pseudouridylation, a process by which uridine — uracil with an attached sugar — is modified to regulate gene expression. Since changes in the abundance of certain H/ACA snoRNAs are characteristic of lung, colorectal, breast, and liver cancer, they may serve as diagnostic biomarkers or therapeutic targets.

The research team profiled H/ACA snoRNA abundance in several mouse cell types and during differentiation in cellular models that included mouse embryonic stem cells and embryonic muscle cells. Using a NanoString nCounter assay to measure their abundance, the scientists identified cell-type specific patterns of H/ACA snoRNA, determined that snoRNA abundance was consistently regulated during differentiation in multiple models, and demonstrated that the observed changes in snoRNA abundance were largely independent of expression of their host genes. The authors proposed a model in which regulated changes in H/ACA snoRNA abundance during cellular differentiation contribute to the production of different ribosomes with distinct pseudouridylation patterns. (RA)

Citation: McCann KL, Kavari SL, Burkholder AB, Phillips BT, Hall TMT. 2020. H/ACA snoRNA levels are regulated during stem cell differentiation. Nucleic Acids Res 48(15):8686–8703.