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Alzheimer’s disease (AD) is a degenerative brain disease that destroys memory and other important mental functions but lacks efficient therapeutic agents. Blocking toxic amyloid β (Aβ) could be beneficial for AD and represents a promising therapeutic strategy for AD treatment. scyllo-Inositol (SI) is a potential therapeutic for AD by directly interacting with the Aβ peptide to inhibit Aβ42 fiber formation. Clinical studies of SI showed promising benefits on mild to moderate AD, however, with limitations on dosage regime. A new strategy to enhance the brain delivery of SI is needed to achieve the efficacy with minimum adverse effects. Herein, we report that a novel guanidine-appended SI derivative AAD-66 resulted in more effective reductions of brain Aβ and plaque deposits, gliosis, and behavioral memory deficits in the disease-established 5xFAD mice. Overall, our present study reveals the potential of AAD-66 as a promising therapeutic agent for AD.

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 high-throughput 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 complex-disease targets that are traditionally deemed "undruggable."

The BBB-permeable trehalose derivative (TD-G6) was found to efficiently prevent the aggregation of polyQ in the transfected HEK293 cells. Furthermore, it was also found to significantly prolong lifespan, improve motor functions, and reduce the inclusion bodies in a transgenic mouse model (Tg R6/2), when given ad libitum.

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.

Herein we report the solid-phase synthesis of a combinatorial aryl, alkyl-triazine library and its application to biofuel production. The combination of Grignard reactions and solid supported Suzuki coupling reactions afforded unique 120 triazine compounds with high purities and minimum purification steps. Through an unbiased phenotypic screening for improved biofuel generation in oleaginous yeast, we found one diaryl triazine derivative (E4) which increased the biolipid production up to 86%.

We synthesized eight G8 molecular transporters (MTs) based on 4 different monosaccharide scaffolds, and studied their biological properties with a special focus on possible mitochondrial targeting and tissue selectivity. The mitochondrial affinity of these MTs was found to be clearly related to the scaffold stereochemistry and also tenuously with the lipophilicity. It may be suggested that in the practical delivery strategy of drugs for the brain and mitochondrial diseases the BBB permeability and mitochondrial affinity should be considered as key parameters, and that an enhanced mitochondrial affinity appears possible by further research on the structure-property relationship of guanidine-rich molecular transporters.

Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, Korea *E-mail: skchung@postech.ac.kr †Department of Chemistry, National University of Singapore, Singapore 117543, Laboratory of Bioimaging Probe Development, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR) Biopolis, Singapore 138667, Singapore Department of Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea Received July 6, 2010, Accepted October 4, 2010

In this study, we investigated the possible use of novel lipidated sorbitol-based transporters as functional devices for the improvement of non-viral gene delivery. These transporters are composed of a sorbitol scaffold bearing 8 guanidine moieties that mimic the arginine residues of well-known cell-penetrating peptides. In addition, the transporters carry different lipid groups to aid DNA condensation and facilitate lipid vesicle-binding. We found that the transporters described in this study have the potential to function as plasmid DNA/siRNA-condensers and surface ligands for the enhancement of cellular uptake of lipid vesicles. Shorter lipid chains were found to be better for condensation, whereas longer chains were superior surface ligands. The differential activity of different cores might be explained by facilitated decondensation of cores prepared with transporters comprised of shorter lipid chains. However, we suggest that there is an optimum value of decondensation to achieve higher transfection activities. The proper use of the transporters presented in this study enabled us to prepare a highly efficient non-viral gene delivery system based on a core-shell structure, in which a condensed DNA core is encapsulated by a lipid envelope. A multifunctional envelope-type nano-device prepared with an optimal surface ligand favorably competes with commonly used transfection systems.

We have synthesized two lactose-based molecular transporters, each containing seven guanidine residues attached to the lactose scaffold through omega-aminocarboxylate linker chains of two different lengths, and have examined their cellular uptakes and intracellular and organellar localizations in HeLa cells, as well as their tissue distributions in mice. Both molecular transporters showed higher cellular uptake efficiencies than Arg8, and wide tissue distributions including the brain. Mitochondrial localization is of special interest because of its potential relevance to "mitochondrial diseases". Interestingly, it has been found that the intracellular localization sites of the G7 molecular transporters-namely either mitochondria or lysosomes and endocytic vesicles-are largely determined by the linker chain lengths, or their associated lipophilicities.

The per oral administration of compound 1, prepared by covalently attaching paclitaxel to a molecular carrier, shows good anti-tumor activity in the orthotopic mouse model of glioblastoma. The anti-tumor effects may be attributable to the cytotoxicity as well as the anti-angiogenic activity of the paclitaxel conjugate or paclitaxel itself in the brain parenchyma.

Novel sucrose-based G7 molecular transporters show different patterns of intracellular localization depending on the nature of the linker chains as well as the fluorescent dyes.

We have developed a novel class of synthetic molecular transport- ers that contain eight residues of guani- dine with an inositol dimer as the scaf- fold. The dimers were prepared by con- necting two units of myo -o rscyllo-ino- sitol via a carbonate or amide linkage, and the multiple units of the guanidine functionality were constructed on the inositol scaffold by means of peracyla- tion with w-aminocarboxylate deriva- tives of varying length. Bioassays based on confocal laser scanning microscopy and fluorescence-activated cell sorter analyses indicated that these transport- ers display a varying degree of mem- brane translocating ability, and the in- tracellular localization and mouse- tissue distribution studies strongly sug- gested that these transporters undergo substantially different mechanistic pro- cesses from those of peptide transport- ers reported to date. It was also shown that doxorubicin, an anticancer antibi- otic, can be efficiently delivered into mouse brain by aid of this type of transporter.