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The Right Tool for the Job
| Content Provider | Semantic Scholar |
|---|---|
| Author | Szewczak, Lara |
| Copyright Year | 2017 |
| Abstract | When you need a Phillips head screw driver, you need a Phillips head screwdriver. You might try to press a flat head into service, but it will be largely ineffective. Tools in biology are no different. The right tool for the job can mean the difference between nailing a biological question or leaving a project in pieces. Chemical tools, in particular, provide ways to acutely probe biological processes. It's difficult to imagine where the cytoskeleton field would be without nocodazole or latrunculin or how well we would understand mRNA transport without leptomycin B. Sadly, however, there's no equivalent of a hardware store for biology, and the tool shelf (such as it is) is sparsely stocked. There are chemical libraries that can be sourced from national centers, commercial sources, or collaborators in industry and academia (see, for example, Jones and Bunnage, 2017xJones, L.H. and Bunnage, M.E. Nat. Rev. Drug Discov. 2017; 16: 285–296Crossref | PubMed | Scopus (12)See all ReferencesJones and Bunnage, 2017). Screening them does yield hits, but the hits may or may not have the necessary specificity, selectivity, or properties to enable use in cells, live animals, or humans. The dilemma is how to pluck effective tools from within the ranks of available molecules or to engineer them.Image from iStockphoto/Floortje.View Large Image | View Hi-Res Image | Download PowerPoint SlideFor many small molecules with phenotypic effects or impacts on specific pathways, the precise molecular targets aren't known, or too many molecular targets have been implicated. New work from Jesse Gray and Michael Springer tackles the latter issue (Boswell et al., 2017xBoswell, S.A., Snavely, A., Landry, H.M., Churchman, L.S., Gray, J.M., and Springer, M. Nat. Chem. Biol. 2017; 13: 501–507Crossref | PubMed | Scopus (2)See all ReferencesBoswell et al., 2017). What can you do when a small molecule shows potent effects in multiple screens aimed at finding inhibitors of dramatically different molecular processes? Is the molecule really promiscuous, or are the individual screens too coarse? Can further studies refine the answer? Gray and Springer's study offers an approach to deconvolute the mechanisms of action for molecules targeting key steps in gene expression—a challenge because transcription, splicing, processing, and transport are interlinked. Using metrics based on analyses of single-strand sequencing data that can distinguish effects on distinct steps, a molecule, isoginkgetin (previously associated with inhibition of both splicing and RNA decay), was surprisingly shown to block transcription elongation. Other elongation inhibitors block CDK9 and control of pause release, but this one is different, and appears to act on a regulatory step later in the transcription process. Although isoginkgetin's molecular target isn't identified, these results point to a new and distinct control point for transcriptional elongation. That's one shiny new addition to the toolkit for probing mechanisms of gene expression.Even when a protein target for a small molecule is well defined, it can be a challenge to ensure it interacts effectively and selectively in vivo—a measure of its ultimate utility. One approach is to capitalize on cellular identity, for example, by targeting a molecule to a cell surface protein that's restricted to a subset of cells. A twist on that is to ectopically tether a molecule to specific cells, where it can interact with endogenous proteins. A recent paper from Michael Tadross and his colleagues focuses on bringing small-molecule inhibitors to the surface of neurons to test how inhibitors affect signaling in specific neuronal populations (Shields et al., 2017xShields, B.C., Kahuno, E., Kim, C., Apostolides, P.F., Brown, J., Lindo, S., Mensh, B.D., Dudman, J.T., Lavis, L.D., and Tadross, M.R. Science. 2017; 356: eaaj2161Crossref | PubMed | Scopus (6)See all ReferencesShields et al., 2017). The approach relies on expression of an optimized version of the HaloTag protein (Los et al., 2008xLos, G.V., Encell, L.P., McDougall, M.G., Hartzell, D.D., Karassina, N., Zimprich, C., Wood, M.G., Learish, R., Ohana, R.F., Urh, M. et al. ACS Chem. Biol. 2008; 3: 373–382Crossref | PubMed | Scopus (602)See all ReferencesLos et al., 2008), a bacterial enzyme engineered to traffic to the cell surface where it interacts selectively with an exogenously supplied ligand. By fusing specific inhibitors to the HaloTag ligand, they become highly enriched on the cells of interest, while proximal cells that lack the expressed HaloTag experience a dramatically lower concentration of the inhibitor and do not respond to it. One application examines how dopamine receptor-expressing cells contribute to the motor symptoms in Parkinson's disease. Impairing AMPAR glutamate receptor signaling in D2 cells of a PD mouse model selectively tempers motor control dysfunction in these mice, establishing dominance of these cells over D1 cells in the circuits controlling motor function. Rapid response is one benefit of this kind of pharmacology. In addition, the targeted proteins are endogenous (of necessity proximal to the ectopically expressed HaloTag) and can be cell-type specific in combination with other resources (e.g., specific Cre lines or precise geographical administration).Every DIY project demands a combination of the right tools and craftiness or inventive problem solving. Questions in biology are just like this. These recent papers showcase how using small-molecule tools can build mechanistic “know-how” around a biological process and, through crafty application, can control where and when molecules encounter their targets to yield answers at the organism scale. |
| File Format | PDF HTM / HTML |
| DOI | 10.1016/j.cell.2017.04.029 |
| PubMed reference number | 28475886 |
| Journal | Medline |
| Volume Number | 169 |
| Alternate Webpage(s) | https://api.elsevier.com/content/article/pii/S009286741730483X |
| Alternate Webpage(s) | https://www.sciencedirect.com/science/article/pii/S009286741730483X |
| Alternate Webpage(s) | https://doi.org/10.1016/j.cell.2017.04.029 |
| Journal | Cell |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
