scholarly journals Bioactive 3D structures of naturally occurring peptides and their application in drug design

2021 ◽  
Vol 85 (1) ◽  
pp. 24-32
Author(s):  
Yuichi Masuda
Keyword(s):  
Drug Design ◽  
3D Structure ◽  
Amyloid Β ◽  
Cell Membrane Permeability ◽  
Amyloid Β Protein ◽  
Nmr Analysis ◽  
3D Structures ◽  
Cyclic Hexapeptide ◽  
Naturally Occurring ◽  
Turn Structure

Abstract Naturally occurring peptides form unique 3D structures, which are critical for their bioactivities. To gain useful insights into drug design, the relationship between the 3D structure and bioactivity of the peptides has been studied. Solid-state nuclear magnetic resonance (NMR) analysis of the 42-residue amyloid β-protein (Aβ42) suggested the presence of toxic conformers with a turn structure at positions 22 and 23 in the aggregates. Antibodies specific to this turn structure could be utilized for immunotherapy and early diagnosis of Alzheimer's disease. Solution NMR analysis of apratoxin A, a cyclic depsipeptide with potent cytotoxicity, proposed an accurate structural model with an important bend structure, which led to the development of highly active mimetics. X-ray crystal analysis of PF1171F, a cyclic hexapeptide with insecticidal activity, indicated the formation of 4 intramolecular hydrogen bonds, which play an important role in cell membrane permeability of PF1171F.

scholarly journals MOLECULAR DOCKING STUDIES FOR THE COMPARATIVE ANALYSIS OF DIFFERENT BIOMOLECULES TO TARGET HYPOXIA INDUCIBLE FACTOR-1α

2017 ◽  
Vol 9 (4) ◽  
pp. 83 ◽  
Author(s):  
Niraj Kumar Jha ◽  
Pravir Kumar
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Hypoxia Inducible Factor ◽  
3D Structure ◽  
Amyloid Β ◽  
Docking Studies ◽  
Therapeutic Window ◽  
Hypoxic Exposure ◽  
Amyloid Β Protein ◽  
Lipinski’S Rule

Objective: Hypoxia plays a significant role in governing many vital signalling molecules in the central nervous system (CNS). Hypoxic exposure has also been depicted as a stimulus for oxidative stress, increase in lipid peroxidation, DNA damage, blood-brain dysfunction, impaired calcium (Ca2+) homoeostasis and agglomeration of oxidized biomolecules in neurons, which act as a novel signature in diverse neurodegenerative and oncogenic processes. On the contrary, the presence of abnormally impaired expression of HIF-1α under hypoxic insult could serve as an indication of the existence of tumors and neuronal dysfunction as well. For instance, under hypoxic stress, amyloid-β protein precursor (AβPP) cleavage is triggered due to the higher expression of HIF-1α and thus leads to synaptic loss. The objective of this research is to perform comparative studies of biomolecules in regulating HIF-1α activity based on in silico approaches that could establish a potential therapeutic window for the treatment of different abnormalities associated with impaired HIF-1α.Methods: We employed various in silico methods such as drug-likeness parameters namely Lipinski filter analysis, Muscle tool, SWISS-MODEL, active site prediction, Auto Dock 4.2.1 and LigPlot1.4.5for molecular docking studies.Results: 3D structure of HIF-1α was generated and Ramachandran plot obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favoured regions. 0% residues in additionally allowed and 0.5% disallowed regions of the HIF-1α protein. Further, initial screenings of the molecules were done based on Lipinski’s rule of five. Cast P server used to predict the ligand binding site suggests that this protein can be utilised as a potential drug target. Finally, we have found Naringenin to be most effective amongst three biomolecules in modulating HIF-1α based on minimum inhibition constant, Ki and highest negative free energy of binding with the maximum interacting surface area during docking studies.Conclusion: The present study outlines the novel potential of Biomolecules in regulating HIF-1α activity for the treatment of different abnormalities associated with impaired HIF-1α.

Properties of cytotoxic peptide-formed ion channels

2000 ◽  
Vol 278 (6) ◽  
pp. C1063-C1087 ◽  
Author(s):  
J. I. Kourie ◽  
A. A. Shorthouse
Keyword(s):  
Ion Channels ◽  
Amyloid Β ◽  
Wolf Spider ◽  
Amyloid Β Protein ◽  
Scorpion Toxins ◽  
Naturally Occurring ◽  
Β Protein ◽  
Skin Secretions ◽  
Β Sheets ◽  
Cytotoxic Peptide

Cytotoxic peptides are relatively small cationic molecules such as those found 1) in venoms, e.g., melittin in bee, scorpion toxins in scorpion, pilosulin 1 in jumper ant, and lycotoxin I and II in wolf spider; 2) in skin secretions (e.g., magainin I and II from Xenopus laevis, dermaseptin from frog, antimicrobials from carp) and cells of the immune system (e.g., insect, scorpion, and mammalian defensins and cryptdins); 3) as autocytotoxicity peptides, e.g., amylin cytotoxic to pancreatic β-cells, prion peptide fragment 106–126 [PrP-(106–126)], and amyloid β-protein (AβP) cytotoxic to neurons; and 4) as designed synthetic peptides based on the sequences and properties of naturally occurring cytotoxic peptides. The small cytotoxic peptides are composed of β-sheets, e.g., mammalian defensins, AβP, amylin, and PrP-(106–126), whereas the larger cytotoxic peptides have several domains composed of both α-helices and β-sheets stabilized by cysteine bonds, e.g., scorpion toxins, scorpion, and insect defensins. Electrophysiological and molecular biology techniques indicate that these structures modify cell membranes via 1) interaction with intrinsic ion transport proteins and/or 2) formation of ion channels. These two nonexclusive mechanisms of action lead to changes in second messenger systems that further augment the abnormal electrical activity and distortion of the signal transduction causing cell death.

Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid β-protein fibrils

2011 ◽  
Vol 19 (20) ◽  
pp. 5967-5974 ◽  
Author(s):  
Yuichi Masuda ◽  
Masashi Fukuchi ◽  
Tatsuya Yatagawa ◽  
Masato Tada ◽  
Kazuyuki Takeda ◽  
...  
Keyword(s):  
Solid State ◽  
Solid State Nmr ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Nmr Analysis ◽  
Interaction Sites ◽  
Β Protein ◽  
Protein Fibrils

Solid-state NMR analysis of the β-strand orientation of the protofibrils of amyloid β-protein

2012 ◽  
Vol 428 (4) ◽  
pp. 458-462 ◽  
Author(s):  
Takashi Doi ◽  
Yuichi Masuda ◽  
Kazuhiro Irie ◽  
Ken-ichi Akagi ◽  
Youko Monobe ◽  
...  
Keyword(s):  
Solid State ◽  
Solid State Nmr ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Nmr Analysis ◽  
Β Protein ◽  
Strand Orientation

scholarly journals Extracellular Protein Aggregates Colocalization and Neuronal Dystrophy in Comorbid Alzheimer’s and Creutzfeldt–Jakob Disease: A Micromorphological Pilot Study on 20 Brains

2021 ◽  
Vol 22 (4) ◽  
pp. 2099
Author(s):  
Nikol Jankovska ◽  
Tomas Olejar ◽  
Radoslav Matej
Keyword(s):  
Prion Protein ◽  
Fluorescent Microscopy ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Key Characteristics ◽  
Jakob Disease ◽  
Immunohistochemical Methods ◽  
Confocal Fluorescent Microscopy ◽  
Codon 129

Alzheimer’s disease (AD) and sporadic Creutzfeldt–Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins—amyloid β-protein (Aβ) and prion protein (PrPSc), respectively. To investigate the potential morphological colocalization of Aβ and PrPSc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrPSc aggregates tended to be, in most cases, located separately, and “compound” plaques were relatively rare. We observed PrPSc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer’s association guidelines, and prion protein subtype with codon 129 methionine–valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrPSc co-aggregates. However, our data showed that PrPSc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques.

scholarly journals A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

2021 ◽  
pp. 1-20
Author(s):  
Yang Yu ◽  
Yang Gao ◽  
Bengt Winblad ◽  
Lars Tjernberg ◽  
Sophia Schedin Weiss
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Three Dimensional ◽  
Amyloid Β ◽  
Stimulated Emission ◽  
Amyloid Β Peptide ◽  
Primary Neurons ◽  
Amyloid Β Protein ◽  
Early Endosomes

Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ 42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the amyloidogenic AβPP processing in primary neurons, including the intracellular pools of the immediate substrate, AβPP C-terminal fragment (APP-CTF) and the product (Aβ 42). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional, three-channel imaging and image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes in soma. Lack of colocalization of Aβ 42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ 42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ 42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

Selective Secretase Targeting for Alzheimer’s Disease Therapy

2021 ◽  
pp. 1-17
Author(s):  
Alvaro Miranda ◽  
Enrique Montiel ◽  
Henning Ulrich ◽  
Cristian Paz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Neuroprotective Activity ◽  
Amyloid Β Protein ◽  
Secretase Activity ◽  
Membrane Bound ◽  
Aβ Production ◽  
Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

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