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Folding and function in ?/?-peptides: targets and therapeutic applications.

ABSTRACT: Combining natural ?-amino acid residues and unnatural ?-amino acid residues in a single chain leads to heterogeneous-backbone oligomers called ?/?-peptides. Despite their unnatural backbones, ?/?-peptides can manifest a variety of folding patterns and biological functions reminiscent of natural peptides and proteins. Moreover, incorporation of ?-residues can impart useful properties to the oligomer such as improved stability to degradation by protease enzymes. ?/?-Peptides have been developed that engage diverse biological targets, including proteins involved in apoptotic signalling, HIV-cell fusion, hormone signalling, and angiogenesis. For some systems, promising results obtained in vitro have paved the way for demonstrated activity in vivo, where ?/?-peptides show equal potency and improved duration of effect compared to ?-peptide counterparts.

SUBMITTER: Werner HM

PROVIDER: S-EPMC4624501 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Publications

Folding and function in α/β-peptides: targets and therapeutic applications.

Werner Halina M HM Horne W Seth WS

Current opinion in chemical biology 20150630

Combining natural α-amino acid residues and unnatural β-amino acid residues in a single chain leads to heterogeneous-backbone oligomers called α/β-peptides. Despite their unnatural backbones, α/β-peptides can manifest a variety of folding patterns and biological functions reminiscent of natural peptides and proteins. Moreover, incorporation of β-residues can impart useful properties to the oligomer such as improved stability to degradation by protease enzymes. α/β-Peptides have been developed th ...[more]

PMID: 26136051

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Project description:The demonstration of chaperone-like activity in peptides (mini-chaperones) derived from ?-crystallin's chaperone region has generated significant interest in exploring the therapeutic potential of peptide chaperones in diseases of protein aggregation. Recent studies in experimental animals show that mini-chaperones could reach intended targets and alter the disease phenotype. Although mini-chaperones show potential benefits against protein aggregation diseases, they do tend to form aggregates on storage. There is thus a need to fine-tune peptide chaperones to increase their solubility, pharmacokinetics, and biological efficacy.This review summarizes the properties and the potential therapeutic roles of mini-chaperones in protein aggregation diseases and highlights some of the refinements needed to increase the stability and biological efficacy of mini-chaperones while maintaining or enhancing their chaperone-like activity against precipitation of unfolding proteins.Mini-chaperones suppress the aggregation of proteins, block amyloid fibril formation, stabilize mutant proteins, sequester metal ions, and exhibit antiapoptotic properties. Much work must be done to fine-tune mini-chaperones and increase their stability and biological efficacy. Peptide chaperones could have a great therapeutic value in diseases associated with protein aggregation and apoptosis.Accumulation of misfolded proteins is a primary cause for many age-related diseases, including cataract, macular degeneration, and various neurological diseases. Stabilization of native proteins is a logical therapeutic approach for such diseases. Mini-chaperones, with their inherent antiaggregation and antiapoptotic properties, may represent an effective therapeutic molecule to prevent the cascade of protein conformational disorders. Future studies will further uncover the therapeutic potential of mini-chaperones. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

Project description:The thermodynamic hypothesis of Anfinsen postulates that structures and stabilities of globular proteins are determined by their amino acid sequences. Chain topology, however, is known to influence the folding reaction, in that motifs with a preponderance of local interactions typically fold more rapidly than those with a larger fraction of nonlocal interactions. Together, the topology and sequence can modulate the energy landscape and influence the rate at which the protein folds to the native conformation. To explore the relationship of sequence and topology in the folding of beta alpha-repeat proteins, which are dominated by local interactions, we performed a combined experimental and simulation analysis on two members of the flavodoxin-like, alpha/beta/alpha sandwich fold. Spo0F and the N-terminal receiver domain of NtrC (NT-NtrC) have similar topologies but low sequence identity, enabling a test of the effects of sequence on folding. Experimental results demonstrated that both response-regulator proteins fold via parallel channels through highly structured submillisecond intermediates before accessing their cis prolyl peptide bond-containing native conformations. Global analysis of the experimental results preferentially places these intermediates off the productive folding pathway. Sequence-sensitive G?-model simulations conclude that frustration in the folding in Spo0F, corresponding to the appearance of the off-pathway intermediate, reflects competition for intra-subdomain van der Waals contacts between its N- and C-terminal subdomains. The extent of transient, premature structure appears to correlate with the number of isoleucine, leucine, and valine (ILV) side chains that form a large sequence-local cluster involving the central beta-sheet and helices alpha2, alpha 3, and alpha 4. The failure to detect the off-pathway species in the simulations of NT-NtrC may reflect the reduced number of ILV side chains in its corresponding hydrophobic cluster. The location of the hydrophobic clusters in the structure may also be related to the differing functional properties of these response regulators. Comparison with the results of previous experimental and simulation analyses on the homologous CheY argues that prematurely folded unproductive intermediates are a common property of the beta alpha-repeat motif.

Dataset Information

Folding and function in ?/?-peptides: targets and therapeutic applications.

Publications

Folding and function in α/β-peptides: targets and therapeutic applications.

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