Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane.
View Article and Find Full Text PDFWnt ligands are critical for tissue homeostasis and form a complex with LRP6 and frizzled coreceptors to initiate Wnt/β-catenin signaling. Yet, how different Wnts achieve various levels of signaling activation through distinct domains on LRP6 remains elusive. Developing tool ligands that target individual LRP6 domains could help elucidate the mechanism of Wnt signaling regulation and uncover pharmacological approaches for pathway modulation.
View Article and Find Full Text PDFHere, we describe the use of peptide backbone -methylation as a new strategy to transform membrane-lytic peptides (MLPs) into cytocompatible intracellular delivery vehicles. The ability of lytic peptides to engage with cell membranes has been exploited for drug delivery to carry impermeable cargo into cells, but their inherent toxicity results in narrow therapeutic windows that limit their clinical translation. For most linear MLPs, a prerequisite for membrane activity is their folding at cell surfaces.
View Article and Find Full Text PDFCell-penetrating peptides (CPPs) are useful tools for the delivery of a wide variety of cargo into cells. Our lab has developed two classes of CPPs based on β-hairpin sequences, one that folds at the surface of cell membranes and the other that is intrinsically disordered. Although these peptides can effectively deliver different types of cargo, their use in protein delivery has been hindered due to the presence of non-natural D-proline within the central turn region of both sequences, which prohibits functionalizing proteins with the CPPs via standard expression protocols.
View Article and Find Full Text PDFProtein biologics are an important class of drugs, but the necessity for frequent parenteral administration is a major limitation. Drug-delivery materials offer a potential solution, but protein-material adsorption can cause denaturation, which reduces their effectiveness. Here, we describe a new protein delivery platform that limits direct contact between globular protein domains and material matrix, yet from a single subcutaneous administration can be tuned for long-term drug release.
View Article and Find Full Text PDFThe repetitive self-assembled structure of amyloid can serve as inspiration to design functional materials. Herein, we describe the design of α/β6, a peptide that contains distinct α-helical and β-structure forming domains. The folding and association state of each domain can be controlled by temperature.
View Article and Find Full Text PDFIn this study, the synthesis of crystalline dodecylguanidine free base and its spectroscopic characterization in nonpolar environments are described. IR as well as H and N NMR spectra of the free base dissolved in aprotic solvents are substantially different from the previously reported spectra of arginine, or other monoalkylguanidinium compounds, at high hydroxide concentrations. The current results provide improved modeling for the spectroscopic signals that would be expected from a deprotonated arginine in a nonpolar environment.
View Article and Find Full Text PDFHere, we report the design, synthesis and efficacy of a new class of ultrasound (US)-sensitive self-assembled peptide-based nanoparticle. Peptisomes are prepared via templated assembly of a de novo designed peptide at the interface of fluorinated nanodroplets. Utilizing peptide assembly allows for facile particle synthesis, direct incorporation of bioactive sequences displayed from the particle corona, and the ability to easily encapsulate biologics during particle preparation using a mild solvent exchange procedure.
View Article and Find Full Text PDFMany cell-penetrating peptides (CPPs) fold at cell surfaces, adopting α- or β-structure that enable their intracellular transport. However, the same structural folds that facilitate cellular entry can also elicit potent membrane-lytic activity, limiting their use in delivery applications. Further, a distinct CPP can enter cells through many mechanisms, often leading to endosomal entrapment.
View Article and Find Full Text PDFOccupation of native ecosystems by invasive plant species alters their structure and/or function. In Hawaii, a subset of introduced plants is regarded as extremely harmful due to competitive ability, ecosystem modification, and biogeochemical habitat degradation. By controlling this subset of highly invasive ecosystem modifiers, conservation managers could significantly reduce native ecosystem degradation.
View Article and Find Full Text PDFThe α-helix is a prevalent secondary structure in proteins and is critical in mediating protein-protein interactions (PPIs). Peptide mimetics that adopt stable helices have become powerful tools for the modulation of PPIs in vitro and in vivo. Hydrogen-bond surrogate (HBS) α-helices utilize a covalent bond in place of an N-terminal i to i+4 hydrogen bond and have been used to target and disrupt PPIs that become dysregulated in disease states.
View Article and Find Full Text PDFOccupation of native ecosystems by invasive plant species alters their structure and/or function. In Hawaii, a subset of introduced plants is regarded as extremely harmful due to competitive ability, ecosystem modification, and biogeochemical habitat degradation. By controlling this subset of highly invasive ecosystem modifiers, conservation managers could significantly reduce native ecosystem degradation.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
May 2014
Helix-coil transition theory connects observable properties of the α-helix to an ensemble of microstates and provides a foundation for analyzing secondary structure formation in proteins. Classical models account for cooperative helix formation in terms of an energetically demanding nucleation event (described by the σ constant) followed by a more facile propagation reaction, with corresponding s constants that are sequence dependent. Extensive studies of folding and unfolding in model peptides have led to the determination of the propagation constants for amino acids.
View Article and Find Full Text PDFStrategically placed covalent linkages have been shown to stabilize helical conformations in short peptide sequences. Here we report the synthesis of a stabilized α-helix that utilizes an internal disulfide linkage. Structural analysis indicates that the dynamic nature of the disulfide bridge allows for the reversible formation of an α-helix through oxidation and reduction reactions.
View Article and Find Full Text PDFBioorg Med Chem Lett
November 2009
Proteases typically recognize their peptide substrates in extended conformations. General approaches for designing protease inhibitors often consist of peptidomimetics that feature this conformation. Herein we discuss a combination of computational and experimental studies to evaluate the potential of triazole-linked beta-strand mimetics as inhibitors of HIV-1 protease activity.
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