STAT3-targeting PROTAC proof of principle for 'undruggables'

The discovery that thalidomide and its analogues work by inducing the degradation of transcription factors demonstrated both that protein degradation is a viable mechanism of action for therapeutic small molecules, and that it could be used to target transcription factors, which are undruggable by both biologics and traditional inhibitors. Proteolysis-targeting chimeras (PROTACs) have joined thalidomide and its analogues as an additional method to induce protein degradation. Now, researchers at the University of Michigan have applied the PROTAC strategy to the transcription factor STAT3. They showed that degrading STAT3 via the PROTAC molecule SD-36 led to regressions in mouse models of lymphoma and leukemia. The team wrote that their work provides "the very first example that the PROTAC technology can turn an essentially undruggable target such as STAT3 into a druggable target, thus paving the way for the design of PROTAC degraders for many other undruggable targets." They reported their results in the Nov. 11, 2019, issue of Cancer Cell.

Integrated stress response backfires in Down syndrome

An individual with Down syndrome inherits all or part of an extra copy of Chromosome 21. Symptoms associated with the syndrome include mental retardation, distinctive facial characteristics, and increased risk for heart defects and digestive problems, which can range from mild to severe. The risk of having a child with Down syndrome rises with the mother’s age at the time of conception. Credit: Darryl Leja, National Human Genome Research Institute, National Institutes of Health

Studies by researchers at Baylor College of Medicine and the University of California at San Francisco have suggested that disturbed protein homeostasis, rather than changed expression levels of one or more proteins, may be the core molecular mechanism underpinning the dysfunctions of Down syndrome (DS). Individuals with Down syndrome have three copies of chromosome 21, which leads to overexpression of a large number of proteins. Furthermore, dysregulated protein expression in Down syndrome is not confined to chromosome 21, suggesting that the mechanisms of deregulated protein expression are complex rather than simply the result of having three chromosomes, rather than two, to transcribe off of. The researchers showed that the integrated stress response (ISR), a mechanism that maintains protein homeostasis, was activated in the brains of both mice and patients with DS, and that "genetic and pharmacological suppression of the ISR, by inhibiting the ISR-inducing double-stranded RNA–activated protein kinase or boosting the function of the eukaryotic translation initiation factor eIF2-eIF2B complex, reversed the changes in translation and inhibitory synaptic transmission and rescued the synaptic plasticity and long-term memory deficits in DS mice. Thus, the ISR plays a crucial role in DS, which suggests that tuning of the ISR may provide a promising therapeutic intervention," the authors wrote. They published their findings in the Nov. 15, 2019, issue of Science.

Size matters in RNA-seq analyses

Between its ability to give a snapshot of cellular activity and to investigate phenomena like alternative splicing, RNA sequencing (RNA-seq) has become a widely used method in modern molecular biology. Now, researchers from Tel Aviv University have demonstrated that current analysis methods do not adequately correct for length-specific effects. Due to the preparation methods for RNA-seq, there is a spurious correlation between gene length and apparent expression level. The authors showed that this correlation was not fully corrected by standard analysis methods, which led to "recurrent false positive calls by gene-set enrichment analysis (GSEA) methods." However, the statistical methods of conditional quantile normalization and EDASeq were able to remove the biases, which reduced false calls. The team reported its findings in the Nov. 12, 2019, issue of PLoS Biology.

Flesh-eating bacteria definitely not better together

Researchers at the University of Texas Medical Branch have gained new insights into how related strains of bacteria can cooperate to worsen outcomes in polymicrobial infections. The new work is built on the previous case study of a patient who required a quadruple amputation after becoming infected with flesh-eating Aeromonas hydrophila. The researchers had previously used metagenomics to show that the patient was infected with two strains, which likely accounted for the severity of infection. In follow-up work, they described the molecular details of how the two strains interacted. Standard diagnostic techniques were unable to distinguish between the two strains, and the authors noted that metagenomic sequencing could prove helpful in cases where infections turn chronic for unknown reasons, as "interaction among microbes of the same species modulates overall bacterial virulence, thus eventually influencing progression of infection and posing challenges in therapeutic interventions." They published their work in the Nov. 11, 2019, online issue of the Proceedings of the National Academy of Sciences.

Gut bacteria can drive heart autoimmunity

Myocarditis is an inflammatory heart disease that can progress to lethal cardiomyopathy. Such progression is marked by the production of autoimmune reactions to the myosin heavy chain muscle protein, but how such autoimmune responses develop has been unclear to date. Now, investigators at the Kantonsspital St. Gallen have shown that these autoimmune reactions appear to be set off by peptides produced by certain members of the gut microbiome. In individuals with certain types of antigen-presenting HLA molecules, peptides produced by commensal microbes can be presented to T cells in what is known as molecular mimicry, setting off responses to the myosin heavy chain. The team concluded that "targeting the microbiome of genetically predisposed myocarditis patients or susceptible patients undergoing checkpoint inhibitor treatment through antibiotics may alleviate disease severity and may therefore help prevent the potentially lethal sequelae of inflammatory cardiomyopathy." Their work appeared in the Nov. 15, 2019, issue of Science.

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