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A variety of methods have been successfully employed to discover bromodomain inhibitors including phenotypic screening, analogue-based design, fragment screening, and many more. More recently, surface plasmon resonance (SPR) has emerged as a primary fragment screening method, which allows direct binding response in real time, with advantage of low sample quantities required and low protein consumption. However, SPR screening has not been routinely applied to bromodomain inhibitor discovery due to solvent used, DMSO, which is also an inhibitor of bromodomains.
The Technology Note by Navratilova et al. (DOI: 10.1021/acsmedchemlett.6b00154) describe the development of a biosensor-based label-free direct screening method for bromodomains. Using a sensitive SPR protocol, the group obtains novel fragment hits, even in the presence of competing DMSO. This technology note adds to the range of approaches that can be applied to the discovery of bromodomain inhibitors.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. It is pathologically characterized by the presence of extracellular plaques composed of aggregated amyloid β peptides (Aβ). To date, the mechanistic connection between protein aggregation and tissue degeneration in the amyloidogenic pathway remain not fully understood. As such, there is ongoing interest in understanding the molecular mechanisms behind Aβ toxicity in order to develop new pharmacological tools targeting the cellular compartment.
In this issue, Simoni et al. (DOI: 10.1021/acsmedchemlett.6b00339) designed a small set of congeners using the polyamine spermine as the vehicle tool to target amyloid aggregation. One compound exhibited effective antiaggregating activity and neuroprotective effects against Aβ-induced toxicity. This study shows the potential for use of polyamine conjugation in understanding the molecular mechanisms involved in mitochondrial Aβ injuries.
There is an increasing interest in developing responsive biomaterials that have flexible physical and chemical properties for applications in drug delivery given that most drugs have specific dosing requirements and that their concentrations must be maintained over an effective range.
In this issue, Park et al. (DOI: 10.1021/acsmedchemlett.6b00293) prepared biocompatible drug carriers in the form of micro-organogels with gold nanorods as a carrier to encapsulate anti-inflammatory drug flurbiprofen, a nonsteroidal anti-inflammatory drug. The group showed accelerated release of flurbiprofen in the presence of near-infrared light due to the increase in the temperature that transforms the gels into liquid. This system highlights a potential versatile scaffold for on-demand drug delivery.