Protein tango: the toolbox to capture interacting partners.
Rutkowska, A. & Schultz, C.
Angew Chem Int Ed Engl. 2012 Aug 13;51(33):8166-76. doi: 10.1002/anie.201201717.Epub 2012 Jun 11.
The evaluation of protein function in the context of the whole cell is crucial for understanding of living systems. In this context, the identification and modulation of protein-protein interactions in and outside cells is of ample importance. Several methods have been developed in the past years to detect and/or actively induce protein-protein interactions in living cells. As a result, tools are now available to manipulate intracellular events by reversible or irreversible cross-linking of proteins in a specific manner. These techniques open many new doors and enable the dissection of complicated protein networks. Herein we describe which cross-linkers and inducers of dimerization are out there and how to make use of this great toolbox.
Target-activated prodrugs for the auto-regulated inhibition of MMP12.
Cobos-Correa, A., Stein, F., Schultz, C.
ACS Med. Chem. Lett., 2012, 3 (8), pp 653-657, doi: 10.1021/ml3001193.
We describe a prodrug concept in which the target enzyme MMP12 produces its own inhibitor in a two-step activation procedure. By using an MMP12-specific peptide sequence and a known sulfonamide drug integrated in the backbone, the active inhibitor is released upon enzyme cleavage. In in vitro experiments, we present proof of concept that the activation proceeds with useful kinetics. The approach is highly selective over the closely related MMP8. If applied in vivo in the future, these prodrugs might release the active entity in a highly specific manner only at such sites where enzyme activity resides.
Spatially resolved monitoring of neutrophil elastase activity with ratiometric fluorescent reporters.
Gehrig, S., Mall, M.A. & Schultz, C.
Angew Chem Int Ed Engl. 2012 Jun 18;51(25):6258-61. doi: 10.1002/anie.201109226.Epub 2012 May 3.
Finding NEmo: In a mouse model for lung inflammation, the lipidated peptide-based ratiometric fluorescent reporter NEmo-2 indicates that neutrophil elastase (NE) activity is mainly associated with the surface of neutrophils, whereas a soluble reporter variant showed no activity in the lung fluid, likely because of the abundance of antiproteases. Targeting the localization of NE activity has great potential for the development of improved antiinflammatory drugs.
Amino acids for diels-alder reactions in living cells.
Plass, T., Milles, S., Koehler, C., Szymanski, J., Mueller, R., Wiessler, M., Schultz, C. & Lemke, E.A.
Angew Chem Int Ed Engl. 2012 Apr 23;51(17):4166-70. doi: 10.1002/anie.201108231.Epub 2012 Mar 30.
Under tension: A set of genetically encoded unnatural amino acids can be used for biocompatible site-specific labeling of proteins with fluorogenic dyes. The new compounds have norbornene and trans-cyclooctene units that react with tetrazine derivatives in an inverse-electron-demand Diels-Alder cycloaddition (left in picture). The technique offers fast labeling that is orthogonal to labeling through azide-cyclooctyne click reaction (right).
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