Special delivery: Transporters constructed on a sorbitol scaffold with eight guanidine residues show significant translocation across the cell membrane and the blood–brain barrier and high affinities toward mitochondria in HeLa and KG1a leukemia cells. The picture shows colocalisation of one such transporter (T) with MitoTracker red in KG1a cells (scale bars: 10 μm).
Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient highthroughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/ inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complexdisease targets that are traditionally deemed "undruggable." chemical biology | drug discovery | helical mimetic
Spezialzustellung: Transporter, die auf einem Sorbitolgerüst mit acht Guanidinresten aufgebaut wurden, zeigen eine signifikante Translokation über die Zellmembran und die Blut‐Hirn‐Schranke sowie hohe Affinitäten gegenüber Mitochondrien in HeLa‐Zellen und KG1a‐Leukämiezellen. In den Bildern ist die Colokalisierung eines solchen Transporters (T) mit MitoTracker (rot) in KG1a‐Zellen gezeigt (Maßstab: 10 μm).
Cell membrane systems represent formidable physical barriers for the trafficking of unintended molecules. Only those molecules with an appropriate range of molecular size, polarity, and charge are allowed to pass through cell membranes. Many potential drug molecules have to overcome these barriers, and a variety of chemical and physical methods have been proposed as means of accomplishing this challenging task. A number of peptides have been reported to
A new class of peptoid-based peptidomimetics composed of oligomers of N-substituted β(2)-homoalanines is reported. Design, solid-phase synthesis, and preliminary circular dichroism studies of oligomers of N-alkylated β(2)-homoalanines consisting of up to 8-mers are described.
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