Dataset Information

Effects of peptides derived from terminal modifications of the a? central hydrophobic core on a? fibrillization.

ABSTRACT: Considerable research effort has focused on the discovery of mitigators that block the toxicity of the ?-amyloid peptide (A?) by targeting a specific step involved in A? fibrillogenesis and subsequent aggregation. Given that aggregation intermediates are hypothesized to be responsible for A? toxicity, such compounds could likely prevent or mitigate aggregation, or alternatively cause further association of toxic oligomers into larger nontoxic aggregates. Herein we investigate the effect of modifications of the KLVFF hydrophobic core of A? by replacing N- and C-terminal groups with various polar moieties. Several of these terminal modifications were found to disrupt the formation of amyloid fibrils and in some cases induced the disassembly of preformed fibrils. Significantly, mitigators that incorporate MiniPEG polar groups were found to be effective against A?(1-40) fibrilligonesis. Previously, we have shown that mitigators incorporating alpha,alpha-disubstituted amino acids (??AAs) were effective in disrupting fibril formation as well as inducing fibril disassembly. In this work, we further disclose that the number of polar residues (six) and ??AAs (three) in the original mitigator can be reduced without dramatically changing the ability to disrupt A?(1-40) fibrillization in vitro.

SUBMITTER: Bett CK

PROVIDER: S-EPMC3368634 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Effects of peptides derived from terminal modifications of the aβ central hydrophobic core on aβ fibrillization.

Bett Cyrus K CK Serem Wilson K WK Fontenot Krystal R KR Hammer Robert P RP Garno Jayne C JC

ACS chemical neuroscience 20100826 10

Considerable research effort has focused on the discovery of mitigators that block the toxicity of the β-amyloid peptide (Aβ) by targeting a specific step involved in Aβ fibrillogenesis and subsequent aggregation. Given that aggregation intermediates are hypothesized to be responsible for Aβ toxicity, such compounds could likely prevent or mitigate aggregation, or alternatively cause further association of toxic oligomers into larger nontoxic aggregates. Herein we investigate the effect of modif ...[more]

PMID: 22778807

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Project description:Multidrug resistant (MDR) pathogen infections are serious threats to hospitalized patients because of the limited therapeutic options. A novel group of antibiotic candidates, antimicrobial peptides (AMPs), have recently shown powerful activities against both Gram-negative and Gram-positive bacteria. Unfortunately, the viability of using these AMPs in clinical settings remains to be seen, since most still need to be evaluated prior to clinical trials and not all of AMPs are potent against MDR clinical isolates. To find a connection between the characteristics of several of these AMPs and their effects against MDR pathogens, we selected 14 AMPs of animal origin with typical structures and evaluated their in vitro activities against clinical strains of extensive drug-resistant Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, extended spectrum ?-lactamase-producing Pseudomonas aeruginosa and extended spectrum ?-lactamase-producing Escherichia coli. Our results showed that these peptides' hydrophilic/hydrophobic characteristics, rather than their secondary structures, may explain their antibacterial effects on these clinical isolates. Peptides that are amphipathic along the longitudinal direction seemed to be effective against Gram-negative pathogens, while peptides with hydrophilic terminals separated by a hydrophobic intermediate section appeared to be effective against both Gram-negative and Gram-positive pathogens. Among these, cathelicidin-BF was found to inhibit all of the Gram-negative pathogens tested at dosages of no more than 16 mg/L, killing a pandrug-resistant A. baumannii strain within 2 h at 4×MICs and 4 h at 2×MICs. Tachyplesin III was also found capable of inhibiting all Gram-negative and Gram-positive pathogens tested at no more than 16 mg/L, and similarly killed the same A. baumannii strain within 4 h at 4×MICs and 2×MICs. These results suggest that both cathelicidin-BF and tachyplesin III are likely viable targets for the development of AMPs for clinical uses.

Project description:Supramolecular hydrogels formed by self-assembly of low molecular weight (LMW) compounds have been identified as promising materials for applications in tissue engineering and regenerative medicine. In many cases, the relationship between the chemical structure of the gelator and the emergent hydrogel properties is poorly understood. As a result, empirical screening strategies instead of rational design approaches are often relied upon to tune the emergent properties of the gels. Herein, we describe a novel strategy to identify improved phenylalanine (Phe) derived gelators using a focused empirical approach. Fluorenylmethoxycarbonyl (Fmoc) protected Phe derivatives are a privileged class of gelators that spontaneously self-assemble into fibrils that entangle to form a hydrogel network upon dissolution into water. However, the Fmoc group has been shown to have toxicity drawbacks for potential biological applications, requiring the identification of new N-terminal modifications that promote efficient self-assembly but lack the shortcomings of the Fmoc group. We previously discovered that fibrils in Fmoc-p-nitrophenylalanine (Fmoc-4-NO2-Phe) hydrogels transition to crystalline microtubes after several hours by a mechanism that involves the hierarchical assembly and fusion of the hydrogel fibrils. We hypothesized that this hierarchical crystallization behavior could form the basis of a screening approach to identify alternative N-terminal functional groups to replace Fmoc in Phe-derived LMW gelators. Specifically, screening N-terminal modifying groups for 4-NO2-Phe that stabilize the hydrogel state by preventing subsequent hierarchical crystallization would facilitate empirical identification of functional Fmoc replacements. To test this approach, we screened a small series of 4-NO2-Phe derivatives with various N-terminal modifying groups to determine if any provided stable LMW supramolecular hydrogels. All but one of the 4-NO2-Phe derivatives assembled into crystalline forms. Only the 1-naphthaleneacetic acid (1-Nap) 4-NO2-Phe derivative self-assembled into a stable hydrogel network. Additional Phe derivatives were modified by N-terminal 1-Nap groups to confirm the general potential of 1-Nap as a suitable replacement for Fmoc, and all derivatives formed stable hydrogels under similar conditions to their Fmoc-Phe counterparts. These results illustrate the potential of this approach to identify next-generation Phe-derived LMW gelators with improved emergent properties.

Dataset Information

Effects of peptides derived from terminal modifications of the a? central hydrophobic core on a? fibrillization.

Publications

Effects of peptides derived from terminal modifications of the aβ central hydrophobic core on aβ fibrillization.

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