β-peptides possess several features that are desirable in peptidomimetics; they are easily synthesized, fold into stable secondary structures in physiologic buffers, and resist proteolysis. They can also bind to a diverse array of proteins to inhibit their interactions with α–helical ligands. β–peptides are not usually cell permeable, however, and this feature limits their utility as research tools and potential therapeutics. Appending an Arg8 sequence to a β–peptide improves uptake but adds considerable mass. We reported that embedding a small cationic patch within a PPII, α– or β–peptide helix improves uptake without the addition of significant mass. In another mass-neutral strategy, Verdine, Walensky, and others have reported that insertion of a hydrocarbon bridge between the i and i+4 positions of an α–helix also increases cell uptake. Here we describe a series of β–peptides containing diether and hydrocarbon bridges and compare them on the basis of cell uptake and localization, affinities for hDM2, and 14-helix structure. Our results highlight the relative merits of cationic patch and hydrophobic bridge strategies for improving β–peptide uptake and identify a surprising correlation between uptake efficiency and hDM2 affinity.

SummaryAdvances in the foldamer field in recent years are as diverse as the backbones of which they are composed. Applications have ranged from cellular penetration and membrane disruption to discrete molecular recognition, while efforts to control the complex geometric shape of foldamers has entered the realm of tertiary and quaternary structure. This review will provide recent examples of progress in the foldamer field, highlighting the significance of this class of compounds and the advances that have been made towards exploiting their full potential.

The use of dichloroacetate (DCA) for treating patients with mitochondrial diseases is limited by the induction of peripheral neuropathy. The mechanisms of DCA-induced neuropathy are not known. Oral DCA treatment (50–500 mg/kg/day for up to 16 weeks) induced tactile allodynia in both juvenile and adult rats; concurrent thermal hypoalgesia developed at higher doses. Both juvenile and adult rats treated with DCA developed nerve conduction slowing that was more pronounced in adult rats. No overt axonal or glial cell abnormalities were identified in peripheral nerves or spinal cord of any DCA-treated rats but morphometric analysis identified a reduction of mean axonal caliber of peripheral nerve myelinated fibers. DCA treatment also caused accumulation of oxidative stress markers in the nerves. These data indicate that behavioral, functional and structural indices of peripheral neuropathy may be induced in both juvenile and adult rats treated with DCA at doses similar to those in clinical use. DCA-induced peripheral neuropathy primarily afflicts axons and involves both metabolic and structural disorders. The DCA-treated rat may provide insight into the pathogenesis of peripheral neuropathy and facilitate development of adjuvant therapeutics to prevent this disorder that currently restricts the clinical use of DCA.

We recently reported a β 3 -decapeptide, βWWI-1, that binds a validated gp41 model in vitro and inhibits gp41-mediated fusion in cell culture. Here we report six analogs of βWWI-1 containing a variety of non-natural side chains in place of the central tryptophan of the WWI-epitope. These analogs were compared on the basis of both gp41 affinity in vitro and fusion inibition in live, HIVinfected cells. One new β 3 -peptide, βWXI-a, offers a significantly improved CC 50 /EC 50 ratio in the live cell assay.Linear peptides derived from the C-terminus of HIV-1 gp41 (C-peptides) are potent HIV fusion inhibitors 1 . These molecules bind to the gp41 N-peptide region and inhibit an intramolecular protein-protein interaction that drives fusion of viral and host cell membranes [2][3][4] . Previous work has shown that the protein-protein interface consists of a highly conserved pocket on the N-peptide surface that is occupied by three C-peptide side chains: Trp-628, Trp-631 and Ile-635 3-5 . These three residues comprise the WWI epitope 3-5 . Simple 6-9 and constrained 10-13 α-peptides, aromatic foldamers 14 , peptide-small molecule conjugates 15 , and small molecules 16,17 that bind this N-peptide surface pocket inhibit gp41-mediated cell fusion with IC 50 values ranging from 250 pM for α-peptides to 5 μM for small molecules. We previously reported a set of β 3 -decapeptides that present a WWI epitope on one face of a salt bridge 18-21 and macrodipole-stabilized 22 14-helix 23,24 . One of these molecules, βWWI-1, binds a validated gp41 model in vitro and inhibits gp41-mediated fusion in cell culture 25 . Past work by Chan and co-workers 6 demonstrated the importance of the three epitope residues, particularly the central tryptophan, in both gp41 affinity and viral infectivity. Here we report six analogs of βWWI-1 containing a variety of nonnatural side chains in place of the central tryptophan of the WWI-epitope. These analogs were compared on the basis of both gp41 affinity in vitro and fusion inibition in live, HIV-infected cells. One new β 3 -peptide, βWXI-a, offers a significantly improved CC 50 /EC 50 ratio in the live cell assay.We synthesized a small collection of β 3 -decapeptides (βWXI-a-f) containing a variety of nonnatural side chains in place of the central tryptophan of the WWI-epitope (Figure 1). These nonnatural residues included those with both entended or alternative π-systems (βWXI-b,d)Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. and halogen-substituted aromatic rings (βWXI-a,c,e,f) to probe the steric and electronic requirements of the N-peptide surface ...

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