A Tau-sand forms of tau?
Investigators at Massachusetts General Hospital have undertaken a detailed characterization of tau from several dozen individuals with Alzheimer’s disease (AD) and found that the characteristics of tau differed among patients in multiple ways. AD progresses at very different speeds in different patients, and clinical progression is correlated with the extent of tau aggregates in the brain. The authors hypothesized that biophysical characteristics might lead to differences in the aggregation-proneness of tau, as well as its ability to seed tangles. They found “striking patient-to-patient heterogeneity” in how well tau from different patients was able to seed tangles, as well as in the ability of tau-targeting antibodies to disrupt that seeding ability. “Different individuals with ‘typical’ AD may have distinct biochemical features of tau,” the authors wrote. “These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.” They reported their results in the June 22, 2020, online issue of Nature Medicine.
P53 ‘glue’ gums up cancer cells
Scientists at the University of California at Berkeley have used activity-based protein profiling (ABPP) to identify a new class of small molecules that could serve as molecular “glue” between the ubiquitin E3 ligase UBR7 and the tumor suppressor p53. Targeting ubiquitin ligases, which mark proteins for destruction by the cellular machinery, to specific proteins to induce their degradation is seen as a promising way to target currently undruggable proteins, but identifying small molecules that can lead to such retargeting is in its infancy. The researchers hypothesized that electrophilic small molecules could be useful glues because they can form covalent bonds with their targets. Screening showed that electrophilic manumycin polyketides were able to target UBR7 to p53, and induce apoptosis of breast cancer cells in vitro. “Our study showcases the possibility that multicovalent small molecules can potentially act as new molecular glues, and that these interactions can be quickly deciphered using chemoproteomic approaches,” the authors wrote. Their work appeared in the June 22, 2020, online issue of Nature Chemical Biology.
Shock and kill with less toxicity
Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) have developed a SMAC mimetic that was optimized as a latency-reversing agent, and they demonstrated that it could activate HIV-infected T cells without causing cytokine release syndrome. Latency reversal or the induction of nonreplicating HIV to return to active proliferation, colloquially known as shock and kill or kick and kill, is one of the key barriers to eradicating HIV in infected individuals. Some latency-reversing agents (LRAs) have been too weak to activate dormantly infected T cells, while those that have been more effective have also induced cytokine release syndrome. The SBP team had previously reported that a SMAC mimetic – a class of small molecules that modulates apoptosis – was able to reverse latency in infected T cells in vitro. Subsequently, they optimized that compound to create Ciapavir (SBI-0953294), and demonstrated that in mice with humanized immune systems, the compound was capable of reversing latency without causing cytokine release syndrome by activating non-canonical NF-κB signaling. The team published its findings in the June 23, 2020, online issue of Cell Reports Medicine.
Placental attachment theory
Researchers at the University of California at San Francisco have identified possible biomarkers for placenta accreta, a pregnancy condition where the placenta invades too deeply into uterine tissue to detach easily during birth. The attachment of the placenta to the uterus needs to be precisely controlled – insufficient attachment increases the risk of pre-eclampsia, while invasive attachment deep into the uterus is dangerous during birth. Cytotrophoblasts (CTBs) are the key cell type that controls attachment, and the authors compared gene expression patterns in CTBs from normal pregnancies and those from the placenta accrete spectrum. They identified the RNA for DOCK4, which is also involved in cell invasiveness in cancer, as being highly up-regulated in placenta accrete spectrum, along with other molecules. Placenta accreta “has significant implications for the mother and fetus. Most often, this includes a preterm delivery to decrease the risk of spontaneous labor and hemorrhage as well as a hysterectomy at the time of C-section. Prenatal diagnosis is crucial so that affected women can deliver at a tertiary care center and with proper planning,” the authors wrote. “As the incidence of PAS rises, the importance of developing a diagnostic biomarker panel that could be assayed using a maternal blood or urine sample increases. This seems feasible given our discovery of numerous CTB genes that are dysregulated in this condition and the fact that excessive invasion of the uterus and its arteries should result in higher circulating levels of placental proteins.” They reported their findings in the June 23, 2020, online issue of the Proceedings of the National Academy of Sciences.