AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Correction: Tsimbalyuk et al. The Intrinsically Disordered W Protein Is Multifunctional during Henipavirus Infection, Disrupting Host Signalling Pathways and Nuclear Import. <i>Cells</i> <b>2020</b>, <i>9</i>, 1913

The authors would like to make the following corrections to the published paper [...

Validation of guidance for the prediction of the directivity index of ventilation louvres

The accurate prediction of external noise levels received at sensitive locations from building services plant is crucial at the design and planning stages of many construction projects. Guidance for the prediction of the directivity index of ventilation louvres found in the literature has been reviewed and partially validated. CIBSE Guide B4 is widely used by acousticians in the UK and other parts of the world. It presents guidance for predicting the directivity index of wall-mounted building ventilation louvres emitting noise to atmosphere at various angles. For louvres of large surface area it predicts very high values of frequency independent attenuation. This is not consistent with theoretical understanding of source directivity. The origin or basis for this correction has not been found in the literature. Experimental results strongly suggested that that the CIBSE B4 prediction method is not accurate for predicting the directivity index of large external ventilation louvres and that the guidance is questionable for small louvres. Of the other prediction methods found in the literature and tested in this study, one method showed stronger agreement with the measurements. Further investigation into this method is proposed to determine its suitability as a valid prediction alternative

Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8⁺ T Cells in Immunotherapy-Resistant and Metastatic Cancers

SIMPLE SUMMARY: Some important signaling proteins that control how cells grow and behave not only act in the cytoplasm but also in the nucleus, where they tether to chromatin. This is especially true for protein kinase C (PKC)-θ, which acts in the nucleus to mediate cancer hallmarks that drive metastasis and in normal T cells. However, current PKC-θ inhibitors are either non-specific or target only its cytoplasmic function. In a bid to develop a novel class of PKC-θ inhibitor that maintains cytoplasmic signaling but inhibits its nuclear function, here we present a novel PKC-θ inhibitor (nPKC-θi2) that specifically inhibits nuclear translocation of PKC-θ without interrupting normal signaling in healthy T cells. We show for the first time that nPKC-θ mediates immunotherapy resistance via its activity in circulating tumor cells and dysfunctional CD8(+) T cells. Our novel inhibitor provides a means to target this process by simultaneously overcoming T-cell exhaustion and cancer stem cell burden. As part of a sequential approach with other therapies, this work paves the way for improving outcomes in cancer patients with immunotherapy-resistant relapse and metastasis. ABSTRACT: Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8(+) T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1(+)/CD8(+) T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ repressive complex to induce cytokine production in CD8(+) T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8(+) T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy

In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting

International audienceIn vitro, ACE2 translocates to the nucleus to induce SARS-CoV-2 replication. Here, using digital spatial profiling of lung tissues from SARS-CoV-2-infected golden Syrian hamsters, we show that a specific and selective peptide inhibitor of nuclear ACE2 (NACE2i) inhibits viral replication two days after SARS-CoV-2 infection. Moreover, the peptide also prevents inflammation and macrophage infiltration, and increases NK cell infiltration in bronchioles. NACE2i treatment increases the levels of the active histone mark, H3K27ac, restores host translation in infected hamster bronchiolar cells, and leads to an enrichment in methylated ACE2 in hamster bronchioles and lung macrophages, a signature associated with virus protection. In addition, ACE2 methylation is increased in myeloid cells from vaccinated patients and associated with reduced SARS-CoV-2 spike protein expression in monocytes from individuals who have recovered from infection. This protective epigenetic scarring of ACE2 is associated with a reduced latent viral reservoir in monocytes/macrophages and enhanced immune protection against SARS-CoV-2. Nuclear ACE2 may represent a therapeutic target independent of the variant and strain of viruses that use the ACE2 receptor for host cell entry