ABSTRACT
Beta-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 alpha-helical ligands. beta-peptides are usually not cell-permeable, however, and this feature limits their utility as research tools and potential therapeutics. Appending an Arg(8) sequence to a beta-peptide improves uptake but adds considerable mass. We previously reported that embedding a small cationic patch within a PPII, alpha-, or beta-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 alpha-helix also increases cell uptake. Here we describe a series of beta-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 the cationic-patch and hydrophobic-bridge strategies for improving beta-peptide uptake and identify a surprising correlation between uptake efficiency and hDM2 affinity.
Subject(s)
Cell Membrane Permeability/drug effects , Peptides/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Computer Simulation , HeLa Cells , Humans , Peptides/chemical synthesis , Peptides/chemistry , Proto-Oncogene Proteins c-mdm2/chemistry , Proto-Oncogene Proteins c-mdm2/metabolism , Structure-Activity Relationship , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/metabolismABSTRACT
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 per 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 rat, but morphometric analysis identified a reduction of mean axonal caliber of peripheral nerve myelinated fibers. Dichloroacetate 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. Dichloroacetate-induced peripheral neuropathy primarily afflicts axons and involves both metabolic and structural disorders. The DCA-treated rat may provide insight into the pathogenesis of this peripheral neuropathy and facilitate development of adjuvant therapeutics to prevent this disorder that currently restricts the clinical use of DCA.
Subject(s)
Dichloroacetic Acid/toxicity , Hypesthesia/chemically induced , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/pathology , Age Factors , Animals , Dichloroacetic Acid/administration & dosage , Dose-Response Relationship, Drug , Electromyography , Female , Foot/innervation , Hypesthesia/pathology , Hypesthesia/physiopathology , Neural Conduction/drug effects , Oxidative Stress/drug effects , Peripheral Nervous System Diseases/physiopathology , Rats , Rats, Sprague-Dawley , Skin/innervationABSTRACT
We recently reported a beta(3)-decapeptide, betaWWI-1, that binds a validated gp41 model in vitro and inhibits gp41-mediated fusion in cell culture. Here we report six analogs of betaWWI-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, HIV-infected cells. One new beta(3)-peptide, betaWXI-a, offers a significantly improved CC(50)/EC(50) ratio in the live cell assay.
Subject(s)
HIV Fusion Inhibitors/chemistry , Peptides/chemistry , Cell Line , HIV Envelope Protein gp41/metabolism , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacology , HIV Infections/drug therapy , HIV-1 , Humans , Peptides/chemical synthesis , Peptides/pharmacology , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Advances 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.