Delivery of mirror image polypeptides into cells

Rabideau, Amy E.; Liao, Xiaoli; Pentelute, Bradley L.

doi:10.1039/c4sc02078b

Cited by 21 publications

(27 citation statements)

References 33 publications

(52 reference statements)

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“…D peptides | transmembrane peptides | racemic crystallization | racemic detergent | coiled coil P olypeptides comprising D-amino acid residues have been sources of growing interest for biological applications, often for functions that depend on recognition by specific natural proteins (1)(2)(3). D peptides offer identical versatility in terms of conformation and side-chain functionality relative to conventional peptides (composed of L-amino acid residues), but D peptides are impervious to the action of proteolytic enzymes, which should improve pharmacokinetic properties in vivo relative to those of conventional peptides.…”

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confidence: 99%

High-resolution structures of a heterochiral coiled coil

Mortenson

Steinkruger

Kreitler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Interactions between polypeptide chains containing amino acid residues with opposite absolute configurations have long been a source of interest and speculation, but there is very little structural information for such heterochiral associations. The need to address this lacuna has grown in recent years because of increasing interest in the use of peptides generated from D amino acids (D peptides) as specific ligands for natural proteins, e.g., to inhibit deleterious proteinprotein interactions. Coiled-coil interactions, between or among α-helices, represent the most common tertiary and quaternary packing motif in proteins. Heterochiral coiled-coil interactions were predicted over 50 years ago by Crick, and limited experimental data obtained in solution suggest that such interactions can indeed occur. To address the dearth of atomic-level structural characterization of heterochiral helix pairings, we report two independent crystal structures that elucidate coiled-coil packing between L-and D-peptide helices. Both structures resulted from racemic crystallization of a peptide corresponding to the transmembrane segment of the influenza M2 protein. Networks of canonical knobs-into-holes side-chain packing interactions are observed at each helical interface. However, the underlying patterns for these heterochiral coiled coils seem to deviate from the heptad sequence repeat that is characteristic of most homochiral analogs, with an apparent preference for a hendecad repeat pattern.D peptides | transmembrane peptides | racemic crystallization | racemic detergent | coiled coil P olypeptides comprising D-amino acid residues have been sources of growing interest for biological applications, often for functions that depend on recognition by specific natural proteins (1-3). D peptides offer identical versatility in terms of conformation and side-chain functionality relative to conventional peptides (composed of L-amino acid residues), but D peptides are impervious to the action of proteolytic enzymes, which should improve pharmacokinetic properties in vivo relative to those of conventional peptides. The engineering of D peptides to display defined protein-binding preferences is hindered, however, by the dearth of experimental information available for such complexes. Structural principles that are well-known to govern interactions between two L-polypeptide chains are not directly extensible to pairings between peptides of opposite chirality. Favorable heterochiral interactions (between L-and D peptides) that are analogous to homochiral associations between L peptides were postulated decades ago on the basis of geometrical considerations (4, 5). In a 1953 analysis of structural parameters governing coiled-coil formation between right-handed α-helices formed from L peptides, for example, Crick suggested that analogous assemblies should be accessible to pairs of right-and left-handed helices (4). In the same year, Pauling and Corey postulated that heterochiral peptide mixtures could form "rippled" β-sheet assemblies with backbo...

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confidence: 99%

High-resolution structures of a heterochiral coiled coil

Mortenson

Steinkruger

Kreitler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Utilizing the PA/LF N delivery system, studies are ongoing to explore the effect of mirror image amino acids on ubiquitin-independent protein degradation including unstructured or destabilizing regions of proteins. 23 …”

Section: Discussionmentioning

confidence: 99%

A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway

Rabideau

Pentelute

2015

ACS Cent. Sci.

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Eukaryotes have evolved the ubiquitin (Ub)/proteasome system to degrade polypeptides. The Ub/proteasome system is one way that cells regulate cytosolic protein and amino acids levels through the recognition and ubiquitination of a protein’s N-terminus via E1, E2, and E3 enzymes. The process by which the N-terminus stimulates intracellular protein degradation is referred to as the N-end rule. Characterization of the N-end rule has been limited to only the natural l-amino acids. Using a cytosolic delivery platform derived from anthrax lethal toxin, we probed the stability of mixed chirality proteins, containing one d-amino acid on the N-terminus of otherwise all l-proteins. In all cases, we observed that one N-terminal d-amino acid stabilized the cargo protein to proteasomal degradation with respect to the N-end rule. We found that since the mixed chirality proteins were not polyubiquitinated, they evaded N-end-mediated proteasomal degradation. Evidently, a subtle change on the N-terminus of a natural protein can enhance its intracellular lifetime.

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“…Recent discovery of potent therapeutic molecules, which did not reach the clinic due to poor delivery and low bioavailability, has made the delivery of such molecules a key issue in therapeutic development. A wide range of different strategies are being explored to achieve this, as such, lipid-derived compounds (pepducins and liposiomes) [ 119 , 120 ], polymeric nanoparticules [ 121 ], inorganic carriers [ 122 , 123 ], super charged proteins [ 124 ], deactivated pathogen toxins [ 125 , 126 ] and, most commonly, cell penetrating peptides (CPP) – like the transactivatior of transcription (TAT) of HIV-1 [ 127 , 128 ]. CPP mechanisms are still poorly understood and the subject of strong controversy [ 127 , 129 ].…”

Section: Introductionmentioning

confidence: 99%

Motif mediated protein-protein interactions as drug targets

Corbi‐Verge

Kim

2016

Cell Commun Signal

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Protein-protein interactions (PPI) are involved in virtually every cellular process and thus represent an attractive target for therapeutic interventions. A significant number of protein interactions are frequently formed between globular domains and short linear peptide motifs (DMI). Targeting these DMIs has proven challenging and classical approaches to inhibiting such interactions with small molecules have had limited success. However, recent new approaches have led to the discovery of potent inhibitors, some of them, such as Obatoclax, ABT-199, AEG-40826 and SAH-p53-8 are likely to become approved drugs. These novel inhibitors belong to a wide range of different molecule classes, ranging from small molecules to peptidomimetics and biologicals. This article reviews the main reasons for limited success in targeting PPIs, discusses how successful approaches overcome these obstacles to discovery promising inhibitors for human protein double minute 2 (HDM2), B-cell lymphoma 2 (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP), and provides a summary of the promising approaches currently in development that indicate the future potential of PPI inhibitors in drug discovery.

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Delivery of mirror image polypeptides into cells

Abstract: Mirror image peptides have unique stability and immunogenic properties in mammals, making them attractive agents to investigate.

Cited by 21 publications

References 33 publications

High-resolution structures of a heterochiral coiled coil

High-resolution structures of a heterochiral coiled coil

A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway

Motif mediated protein-protein interactions as drug targets

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