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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(38):11664-11668
Racemates often have lower solubility than enantiopure compounds, and the mixing of enantiomers can enhance the aggregation propensity of peptides. Amyloid beta (Aβ) 42 is an aggregation‐prone peptide that is believed to play a key role in Alzheimer's disease. Soluble Aβ42 aggregation intermediates (oligomers) have emerged as being particularly neurotoxic. We hypothesized that the addition of mirror‐image d ‐Aβ42 should reduce the concentration of toxic oligomers formed from natural l ‐Aβ42. We synthesized l ‐ and D ‐Aβ42 and found their equimolar mixing to lead to accelerated fibril formation. Confocal microscopy with fluorescently labeled analogues of the enantiomers showed their colocalization in racemic fibrils. Owing to the enhanced fibril formation propensity, racemic Aβ42 was less prone to form soluble oligomers. This resulted in the protection of cells from the toxicity of l ‐Aβ42 at concentrations up to 50 μm . The mixing of Aβ42 enantiomers thus accelerates the formation of non‐toxic fibrils. 相似文献
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Zhangyong Si Hui Wen Lim Moon Y. F. Tay Yu Du Lin Ruan Haofeng Qiu Rubí Zamudio-Vazquez Sheethal Reghu Yahua Chen Wen Shuo Tiong Kalisvar Marimuthu Partha Pratim De Oon Tek Ng Prof. Yabin Zhu Prof. Yunn-Hwen Gan Prof. Yonggui Robin Chi Prof. Hongwei Duan Prof. Guillermo C. Bazan Prof. E. Peter Greenberg Prof. Mary B. Chan-Park Prof. Kevin Pethe 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(17):6886-6893
Carbapenem-resistant Gram-negative bacteria (GNB) are heading the list of pathogens for which antibiotics are the most critically needed. Many antibiotics are either unable to penetrate the outer-membrane or are excluded by efflux mechanisms. Here, we report a cationic block β-peptide (PAS8-b-PDM12) that reverses intrinsic antibiotic resistance in GNB by two distinct mechanisms of action. PAS8-b-PDM12 does not only compromise the integrity of the bacterial outer-membrane, it also deactivates efflux pump systems by dissipating the transmembrane electrochemical potential. As a result, PAS8-b-PDM12 sensitizes carbapenem- and colistin-resistant GNB to multiple antibiotics in vitro and in vivo. The β-peptide allows the perfect alternation of cationic versus hydrophobic side chains, representing a significant improvement over previous antimicrobial α-peptides sensitizing agents. Together, our results indicate that it is technically possible for a single adjuvant to reverse innate antibiotic resistance in all pathogenic GNB of the ESKAPE group, including those resistant to last resort antibiotics. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(33):9948-9951
Amyloid‐β peptide (Aβ) isoforms of different lengths and aggregation propensities coexist in vivo. These different isoforms are able to nucleate or frustrate the assembly of each other. N‐terminally truncated Aβ(11–40) and Aβ(11–42) make up one fifth of plaque load yet nothing is known about their interaction with full‐length Aβ(1–40/42). We show that in contrast to C‐terminally truncated isoforms, which do not co‐fibrillize, deletions of ten residues from the N terminus of Aβ have little impact on its ability to co‐fibrillize with the full‐length counterpart. As a consequence, N‐terminally truncated Aβ will accelerate fiber formation and co‐assemble into short rod‐shaped fibers with its full‐length Aβ counterpart. This has implications for the assembly kinetics, morphology, and toxicity of all Aβ isoforms. 相似文献
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Chao Ma Juanjuan Su Yao Sun Yang Feng Nolan Shen Bo Li Yingxia Liang Xintong Yang Hui Wu Hongjie Zhang Andreas Herrmann Rudolph E. Tanzi Kai Liu Can Zhang 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(51):18876-18882
Alzheimer's disease (AD) is a neurodegenerative disorder and the primary cause of age‐related dementia. The etiology of AD is complex and has not been completely elucidated. Herein, we report that treatment with elastin‐like polypeptides (ELPs), a component of the brain extracellular matrix (ECM), significantly increased the levels of AD‐related amyloid‐β peptides (Aβ) both in vitro and in vivo. Regarding the molecular mechanism(s), the upregulation of Aβ levels was related to increased proteolytic processing of the amyloid precursor protein. Furthermore, nesting tests demonstrated that the ELP‐treated animals showed significant neurobehavioral deficits with cognitive impairment. These results suggest that the elastin is associated with AD‐related pathological and behavioral changes. This finding presents a new aspect for Alzheimer's amyloidosis event and provides a great promise in developing ELP‐based model systems to better understand the pathogenesis of AD. 相似文献
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Sidechain adapted β-turn mimics of type 1 characterised by a fixed cis-conformation of the peptide chain in the aminopiperidinonecarboxylate scaffold have been synthesised from pyrazinones in order to perform a β-turn scan of the messenger region of substance P. The synthesis of a substance P peptide analogue is also described. 相似文献
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