Acid test for therapeutic peptides
Scientists at the Ecole Polytechnique Fédérale de Lausanne (EPFL) have developed a method to identify peptides that were stable in the gastrointestinal tract, potentially paving the way for the broader development of orally administered peptides. There are a few examples of peptides that remain therapeutically active after oral administration, such as the diabetes drug semaglutide and the antibiotic cyclosporine. However, most peptides are digested too easily to be of any therapeutic use if they are administered orally. In order to identify peptides that could survive in the GI tract, the authors screened a large library of peptides with two cysteine-cysteine bonds, a feature that had increased stability in previous work. High-affinity hits were then exposed to simulated intestinal fluid. Peptides that survived that test were tested in vivo. The authors identified both inhibitors of coagulation factor XIa and the interleukin-23 receptor, and they concluded that “the de novo generation of targeted peptides that resist proteolytic degradation in the gastrointestinal tract should help the development of effective peptides for oral delivery.” Their work appeared in the May 11, 2020, online issue of Nature Biomedical Engineering.
Designer proteins for RSV vaccine
Researchers at the Ecole Polytechnique Fédérale de Lausanne (EPFL) have developed an approach to protein design that allowed them to generate antigens that could induce neutralizing antibodies to respiratory syncytial virus (RSV). Induction of a precise antibody response remains a major unmet challenge for vaccine design, and the immune response to natural proteins is not always focused on those epitopes that will ultimately lead to the strongest immune defense. The team developed a protein design algorithm, named Topobuilder, that they used to engineer proteins with structurally complex epitopes, and used it to develop a three-component RSV vaccine. In vivo, the vaccine induced an antibody response against all three epitopes, resulting in consistent levels of serum neutralization in six of seven nonhuman primates. Though the method will require optimization to increase the magnitude of the response, “our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs,” the authors wrote. They reported their results in the May 15, 2020, issue of Science.
Subdividing and conquering PDAC
Investigators at the University of Glasgow have identified epigenetic biomarkers that could subdivide pancreatic ductal adenocarcinoma according to its sensitivity to inhibitors of glycogen synthase kinase 3b (GSK3b). Pancreatic cancer has been divided into two broad classes, classical and squamous, but so far the relationship of subtypes to either each other or drug sensitivity remains poorly understood. In their work, the authors used a mix of transcriptome and epigenetic profiling of patient-derived cell lines to show that the cells could switch between subtypes due to metabolic rewiring, and that the squamous subtype could be further subdivided according to whether cells were sensitive to GSK3b inhibitors. “Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.” They reported their results in the May 12, 2020, print issue of Cell Reports.
The world according to GARP
Scientists at the University of Cambridge and the Wellcome Sanger Institute have discovered the molecular underpinning of a GWAS autoimmune risk locus on human chromosome 11. Variations at 11q13.5 are linked to the risk of multiple autoimmune diseases, but how that noncoding region affects risk has remained unclear. The authors showed that a region within 11q13.5 functioned as an enhancer that affected levels of glycoprotein A repetitions predominant (GARP) protein in regulatory T cells. The enhancer interacted with the promoter region directly upstream of the gene for GARP, and affected both histone acetylation and GARP expression levels. The authors wrote that their findings “provide a mechanistic basis for association of the 11q13.5 risk locus with immune-mediated diseases and identify GARP as a potential target in their therapy.” Their study was published in the May 14, 2020, issue of Nature.
Cell competition links hyperinsulinemia to cancer
Researchers at the University of Kyoto have discovered a mechanistic link between metabolic diseases, such as type 2 diabetes mellitus (T2DM) and obesity, and an increased risk of cancer risk via systemic regulation of cell competition. Metabolic diseases, including T2DM, glucose intolerance and obesity, are often accompanied by hyperinsulinemia, which has been associated with an increased incidence of cancer. The underlying mechanisms of how hyperinsulinemia promotes tumor growth and malignancy, remain largely unknown. The scientists showed that flies heterozygous for the insulin receptor substrate chico could evade cell competition signals that prevented overgrowth. Pharmacological repression of protein synthesis with diabetes drug metformin prevented hyperinsulinemia-induced scrib overgrowth in the flies. The team reported its results in the May 7, 2020, online edition of Developmental Cell.