This opens the door to applications such as synthetically introducing identified gene variants into plant genomes to produce crops with improved resistance or better stress tolerance properties.
We wish to estimate the extent of multiple-lethality phenomena in similar lines to the experiments of Tong et al. [ 10], that systematically crossed mutations in ~130 different query genes into a set of ~4700 viable gene yeast deletion mutants and identified synthetically lethal or sick interactions.
Optimization of a easily synthetically accessible hit (1) identified by application of a high-throughput docking approach afforded the promising compounds 6 and 8 which proved to inhibit both the helicase and ATPase activity of DDX3 and to reduce the viral load of peripheral blood mononuclear cells (PBMC) infected with HIV-1.
However, plutonium, produced synthetically in 1940, was identified in trace quantities as a naturally occurring primordial element in 1971, and by 2011 it was known that all the elements up to californium can occur naturally as trace amounts in uranium ores by neutron capture and beta decay.
In addition, it has been demonstrated that medicinal chemists are not very consistent in identifying synthetically unfeasible compounds [5 7].
Genes that we identified as inviable (synthetic lethality; SL) or slow growing (synthetically sick; SS or weakly synthetically sick; WSS) when combined with mps3 -Y502H, mps3 -A540D, mps3 -F592S, or mps3 Δ75-150 are listed in Table S1.
Some of the latter are identified in libraries of synthetically accessible molecules by the MED-Search software.
A pooled kinase shRNA library screen was performed and next-generation deep sequencing efforts identified that PRKDC was synthetically lethal in cells overexpressing MYC.
To illustrate this approach, we identified potentially druggable genes synthetically lethal for p53 using three microarray datasets for gene expression profiles of the NCI-60 cancer cell lines, one next-generation sequencing (RNA-Seq) dataset from the Cancer Genome Atlas (TCGA) project, and one gene expression data from the Cancer Cell Line Encyclopedia (CCLE) project.
Similarly, a screen for small molecules that are synthetically lethal with MYC overexpression has identified various compounds interfering with the MYC pathway at different levels, termed MYRAs (MYC pathway response agents), which have subsequently been shown to also selectively target the MYCN pathway [ 108, 109].
