Inhibition and disintegration of insulin amyloid fibrils: a facile supramolecular strategy with p-sulfonatocalixarenes

2016 ◽  
Vol 52 (14) ◽  
pp. 2992-2995 ◽  
Author(s):  
Meenakshi N. Shinde ◽  
Nilotpal Barooah ◽  
Achikanath C. Bhasikuttan ◽  
Jyotirmayee Mohanty
Keyword(s):  
Human Insulin ◽  
Therapeutic Strategy ◽  
Amyloid Fibrils ◽  
Fibril Formation

This study reveals the ability of p-sulfonatocalix[4/6]arenes to effectively inhibit the fibril formation in human insulin and demonstrate its potential to disintegrate/dissolve the mature fibrils, a promising supramolecular therapeutic strategy for amyloidosis.

scholarly journals Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation

2004 ◽  
Vol 377 (3) ◽  
pp. 709-716 ◽  
Author(s):  
Emma T. A. S. JAIKARAN ◽  
Melanie R. NILSSON ◽  
Anne CLARK
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Fibrils ◽  
Secretory Granules ◽  
Pancreatic Beta Cell ◽  
Islet Amyloid Polypeptide ◽  
Fibril Formation ◽  
Islet Amyloid ◽  
Β Sheet

Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.

scholarly journals ADS-J1 Inhibits Semen-Derived Amyloid Fibril Formation and Blocks Fibril-Mediated Enhancement of HIV-1 Infection

2015 ◽  
Vol 59 (9) ◽  
pp. 5123-5134 ◽  
Author(s):  
Tianrong Xun ◽  
Wenjuan Li ◽  
Jinquan Chen ◽  
Fei Yu ◽  
Wei Xu ◽  
...  
Keyword(s):  
Viral Infection ◽  
Amyloid Fibrils ◽  
Synergistic Effects ◽  
Sexual Transmission ◽  
Prostatic Acid Phosphatase ◽  
Fibril Formation ◽  
Antiretroviral Drugs ◽  
Target Cells ◽  
Additional Function ◽  
Hiv 1

ABSTRACTSemen-derived enhancer of viral infection (SEVI) is composed of amyloid fibrils that can greatly enhance HIV-1 infectivity. By its cationic property, SEVI promotes viral sexual transmission by facilitating the attachment and internalization of HIV-1 to target cells. Therefore, semen-derived amyloid fibrils are potential targets for microbicide design. ADS-J1 is an anionic HIV-1 entry inhibitor. In this study, we explored an additional function of ADS-J1: inhibition of SEVI fibril formation and blockage of SEVI-mediated enhancement of viral infection. We found that ADS-J1 bound to an amyloidogenic peptide fragment (PAP248–286, comprising amino acids 248 to 286 of the enzyme prostatic acid phosphatase), thereby inhibiting peptide assembly into amyloid fibrils. In addition, ADS-J1 binds to mature amyloid fibrils and antagonizes fibril-mediated enhancement of viral infection. Unlike cellulose sulfate, a polyanion that failed in clinical trial to prevent HIV-1 sexual transmission, ADS-J1 shows no ability to facilitate fibril formation. More importantly, the combination of ADS-J1 with several antiretroviral drugs exhibited synergistic effects against HIV-1 infection in semen, with little cytotoxicity to vaginal epithelial cells. Our results suggest that ADS-J1 or a derivative may be incorporated into a combination microbicide for prevention of the sexual transmission of HIV-1.

scholarly journals Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity

2019 ◽  
Vol 2 (5) ◽  
pp. e201900486 ◽  
Author(s):  
Justine Lempart ◽  
Eric Tse ◽  
James A Lauer ◽  
Magdalena I Ivanova ◽  
Alexandra Sutter ◽  
...  
Keyword(s):  
Extracellular Space ◽  
Therapeutic Strategy ◽  
Neuronal Cells ◽  
Lewy Bodies ◽  
Fibril Formation ◽  
Amyloid Protein ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Fibril Morphology ◽  
Rate Limiting

The universally abundant polyphosphate (polyP) accelerates fibril formation of disease-related amyloids and protects against amyloid cytotoxicity. To gain insights into the mechanism(s) by which polyP exerts these effects, we focused on α-synuclein, a well-studied amyloid protein, which constitutes the major component of Lewy bodies found in Parkinson’s disease. Here, we demonstrate that polyP is unable to accelerate the rate-limiting step of α-synuclein fibril formation but effectively nucleates fibril assembly once α-synuclein oligomers are formed. Binding of polyP to α-synuclein either during fibril formation or upon fibril maturation substantially alters fibril morphology and effectively reduces the ability of α-synuclein fibrils to interact with cell membranes. The effect of polyP appears to be α-synuclein fibril specific and successfully prevents the uptake of fibrils into neuronal cells. These results suggest that altering the polyP levels in the extracellular space might be a potential therapeutic strategy to prevent the spreading of the disease.

scholarly journals The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

2021 ◽  
Vol 118 (3) ◽  
pp. e2014442118
Author(s):  
Nir Salinas ◽  
Einav Tayeb-Fligelman ◽  
Massimo D. Sammito ◽  
Daniel Bloch ◽  
Raz Jelinek ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Membrane Damage ◽  
Fibril Formation ◽  
Regulation Mechanism ◽  
Bacterial Cells ◽  
Amyloid Fibril Formation ◽  
Β Amyloid ◽  
Β Sheets

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.

Photo-oxygenation inhibits tau amyloid formation

2019 ◽  
Vol 55 (44) ◽  
pp. 6165-6168 ◽  
Author(s):  
Takanobu Suzuki ◽  
Yukiko Hori ◽  
Taka Sawazaki ◽  
Yusuke Shimizu ◽  
Yu Nemoto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Therapeutic Strategy ◽  
Fibril Formation ◽  
Amyloid Formation

Amyloid-selective catalytic photo-oxygenation of the tau protein is a possible therapeutic strategy for Alzheimer's disease, via the inhibition of tau fibril formation.

scholarly journals Adsorption of unfolded Cu/Zn superoxide dismutase onto hydrophobic surfaces catalyzes its formation of amyloid fibrils

2019 ◽  
Vol 32 (2) ◽  
pp. 77-85
Author(s):  
Mohammad Ashhar I Khan ◽  
Ulrich Weininger ◽  
Sven Kjellström ◽  
Shashank Deep ◽  
Mikael Akke
Keyword(s):  
Superoxide Dismutase ◽  
Surface Area ◽  
Amyloid Fibrils ◽  
Hydrophobic Surface ◽  
Fibril Formation ◽  
Hydrophobic Surfaces ◽  
Molecular Features ◽  
Denaturant Concentration

Abstract Intracellular aggregates of superoxide dismutase 1 (SOD1) are associated with amyotrophic lateral sclerosis. In vivo, aggregation occurs in a complex and dense molecular environment with chemically heterogeneous surfaces. To investigate how SOD1 fibril formation is affected by surfaces, we used an in vitro model system enabling us to vary the molecular features of both SOD1 and the surfaces, as well as the surface area. We compared fibril formation in hydrophilic and hydrophobic sample wells, as a function of denaturant concentration and extraneous hydrophobic surface area. In the presence of hydrophobic surfaces, SOD1 unfolding promotes fibril nucleation. By contrast, in the presence of hydrophilic surfaces, increasing denaturant concentration retards the onset of fibril formation. We conclude that the mechanism of fibril formation depends on the surrounding surfaces and that the nucleating species might correspond to different conformational states of SOD1 depending on the nature of these surfaces.

Prion Protein Aggregation Induced by Copper(II) and Heparan Sulfate. Pressure-dependent Switch of Reaction Pathways

2008 ◽  
Vol 63 (6) ◽  
pp. 747-755 ◽  
Author(s):  
Driss El Moustaine ◽  
Joan Torrent ◽  
Reinhard Lange
Keyword(s):  
Heparan Sulfate ◽  
Prion Protein ◽  
Conformational Changes ◽  
Atmospheric Pressure ◽  
Amyloid Fibrils ◽  
Copper Ions ◽  
Fibril Formation ◽  
Cellular Prion Protein ◽  
Reaction Pathways ◽  
Structural Alterations

Copper ions (Cu2+) and heparan sulfate (HS) are suspected to act as regulatory agents in the conversion of cellular prion protein (PrPC) to its infectious isoform. However, the mechanism of this reaction is still largely unknown. Our previous report suggested multidimensional pathways for structural alterations of PrP, which may be modulated by high pressure (HP). Here we use HP to investigate the effects of Cu2+ and HS binding on PrP conformational changes and assembly. In the presence of Cu2+, amyloid fibrils are formed only under HP. In contrast, in the presence of HS, fibrils are formed at atmospheric pressure, but not under HP. Both compounds appear to compete for the same binding site, since HS-supported fibril formation is quenched by Cu2+. Inversely, Cu2+- mediated fibril formation under HP is inhibited by HS.

scholarly journals Study of Nanofibrils Formation of Fibroin Protein in Specific Thermal and Acidity Conditions

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
M Ahrami
Keyword(s):  
Electron Microscopy ◽  
Amyloid Fibrils ◽  
Thermal Conditions ◽  
Fibril Formation ◽  
Fibrillar Structure ◽  
Transmission Electron ◽  
Vis Spectroscopy ◽  
Wide Range ◽  
Model Protein ◽  
Bombyx Mori Silk

Abstract Background: Amyloid fibrils are insoluble arranged aggregates of proteins that are fibrillar in structure and related to many diseases (at least 20 types of illnesses) and also create many pathologic conditions. Therefore understanding the circumstance of fibril formation is very important. Objectives: This study aims to work on fibrillar structure formation of fibroin (as a model protein). Material and Methods: In this experimental study, fibroin was extracted from bombyx mori silk cocoon, and the concentration was obtained by Bradford method. The protein was incubated in a wide range of times (0 min to 7 days) in specific acidity and thermal conditions (pH=1.6, T=70 °C). The assays of UV-vis spectroscopy with congo red, field emission scanning electron microscopy, transmission electron microscopy, atomic force microscopy and circular dichroism spectroscopy were employed to monitor the fibrillation process. Results: Fibroin assemblies were formed upon the process of aggregation and fibril formation with a variety of morphology ranging from nanoparticles to elongated fibrils. Conclusion: The results showed progressive pathway of fibril formation.

scholarly journals Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules

2020 ◽  
Author(s):  
Emma Cawood ◽  
Nicolas Guthertz ◽  
Jessica Ebo ◽  
Theodoros Karamanos ◽  
Sheena E. Radford FRS ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Structural Characterization ◽  
Self Assembly ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Fibril Formation ◽  
X Ray Crystallography ◽  
Starting Point ◽  
Amyloid Assembly

<p></p><p>Protein-protein interactions (PPIs) are involved in many of life’s essential biological functions yet are also an underlying cause of several human diseases, including amyloidosis. The modulation of PPIs presents opportunities to gain mechanistic insights into amyloid assembly, particularly through the use of methods which can trap specific intermediates for detailed study. Such information can also provide a starting point for drug discovery. Here, we demonstrate that covalently tethered small molecule fragments can be used to stabilize specific oligomers during amyloid fibril formation, facilitating the structural characterization of these assembly intermediates. We exemplify the power of covalent tethering using the naturally occurring truncated variant (ΔN6) of the human protein β2-microglobulin (β2m), which assembles into amyloid fibrils associated with dialysis-related amyloidosis. Using this approach, we have trapped tetramers formed by ΔN6 under conditions which would normally lead to fibril formation and found that the degree of tetramer stabilization depends on the site of the covalent tether and the nature of the protein-fragment interaction. The covalent protein-ligand linkage enabled structural characterization of these trapped oligomeric species using X-ray crystallography and NMR, providing insight into why tetramer stabilization inhibits amyloid assembly. Our findings highlight the power of “post-translational chemical modification" as a tool to study biological molecular mechanisms. </p><br><p></p>

scholarly journals Modification of insulin amyloid aggregation by Zr phthalocyanines functionalized with dehydroacetic acid derivatives

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0243904
Author(s):  
Svitlana Chernii ◽  
Yuriy Gerasymchuk ◽  
Mykhaylo Losytskyy ◽  
Damian Szymański ◽  
Iryna Tretyakova ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Cluster Formation ◽  
Aromatic Amino Acids ◽  
Functional Materials ◽  
Fibril Formation ◽  
Dehydroacetic Acid ◽  
Protein Fibrils ◽  
Conformational Disorders ◽  
Free Insulin ◽  
Out Of Plane

Amyloid fibrils are widely studied both as target in conformational disorders and as basis for the development of protein-based functional materials. The three Zr phthalocyanines bearing dehydroacetic acid residue (PcZr(L1)2) and its condensed derivatives (PcZr(L2)2 and PcZr(L3)2) as out-of-plane ligands were synthesized and their influence on insulin fibril formation was studied by amyloid-sensitive fluorescent dye based assay, scanning electron microscopy, fluorescent and absorption spectroscopies. The presence of Zr phthalocyanines was shown to modify the fibril formation. The morphology of fibrils formed in the presence of the Zr phthalocyanines differs from that of free insulin and depends on the structure of out-of-plane ligands. It is shown that free insulin mostly forms fibril clusters with the length of about 0.3–2.1 μm. The presence of Zr phthalocyanines leads to the formation of individual 0.4–2.8 μm-long fibrils with a reduced tendency to lateral aggregation and cluster formation (PcZr(L1)2), shorter 0.2–1.5 μm-long fibrils with the tendency to lateral aggregation without clusters (PcZr(L2)2), and fibril-like 0.2–1.0 μm-long structures (PcZr(L3)2). The strongest influence on fibrils morphology made by PcZr(L3)2 could be explained by the additional stacking of phenyl moiety of the ligand with aromatic amino acids in protein. The evidences of binding of studied Zr phthalocyanines to mature fibrils were shown by absorption spectroscopy (for PcZr(L1)2 and PcZr(L2)2) and fluorescent spectroscopy (for PcZr(L3)2). These complexes could be potentially used as external tools allowing the development of functional materials on protein fibrils basis.

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