4 research outputs found
Development of a Scalable Synthesis of HP-β-CD Pluronic Polyrotaxanes
Polyrotaxanes are polymers that have macrocycles threaded onto them, analogous to beads threaded onto a string. These materials are used for a variety of different biomedical applications.1-3 The Thompson group has been developing 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) polyrotaxanes as therapeutics for the treatment of Niemann-Pick Type C (NPC) disease. NPC is a debilitating genetic disorder where cholesterol accumulates in the lysosomes of cells.4 Developing a scalable process is crucial for the advancement of these materials as NPC therapeutics. The goal of this project is to optimize the only protocol for the synthesis of HP-β-CD/Pluronic polyrotaxanes in order to develop a synthetic method that can be operated on the multi-gram scale to support preclinical studies.5 Each component of the protocol was screened to determine which combination lead to the formation of polyrotaxanes with the highest yields and threading efficiencies in the shortest amount of time. Threading efficiency is a measure of how many HP-β-CD molecules are threaded onto each polymer. In addition to optimizing the current protocol, we have also explored flowing the reaction mixture through a bath sonicator and using a hydraulic press as alternative syntheses. It was found that probe sonication and bath sonication are both necessary components of the protocol. This indicates that sufficient agitation of the reaction mixture is required to promote the non-covalent threading reaction. Furthermore, bath sonication for one hour, followed by stirring for two days gave the highest threading efficiency. The results of these studies have simplified the existing protocol, but additional studies are needed to reveal whether this protocol is robust enough for efficient preparation of other HP-β-CD/Pluronic polyrotaxane derivatives
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A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila.
Huntington disease is caused by the expansion of a polyglutamine repeat in the Huntingtin protein (Htt) that leads to degeneration of neurons in the central nervous system and the appearance of visible aggregates within neurons. We have developed and tested suppressor polypeptides that bind mutant Htt and interfere with the process of aggregation in cell culture. In a Drosophila model, the most potent suppressor inhibits both adult lethality and photoreceptor neuron degeneration. The appearance of aggregates in photoreceptor neurons correlates strongly with the occurrence of pathology, and expression of suppressor polypeptides delays and limits the appearance of aggregates and protects photoreceptor neurons. These results suggest that targeting the protein interactions leading to aggregate formation may be beneficial for the design and development of therapeutic agents for Huntington disease
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A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila.
Huntington disease is caused by the expansion of a polyglutamine repeat in the Huntingtin protein (Htt) that leads to degeneration of neurons in the central nervous system and the appearance of visible aggregates within neurons. We have developed and tested suppressor polypeptides that bind mutant Htt and interfere with the process of aggregation in cell culture. In a Drosophila model, the most potent suppressor inhibits both adult lethality and photoreceptor neuron degeneration. The appearance of aggregates in photoreceptor neurons correlates strongly with the occurrence of pathology, and expression of suppressor polypeptides delays and limits the appearance of aggregates and protects photoreceptor neurons. These results suggest that targeting the protein interactions leading to aggregate formation may be beneficial for the design and development of therapeutic agents for Huntington disease