Interaction of the anthracycline 4'-iodo-4'-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis.

Merlini, Giampaolo; Ascari, E; Amboldi, Nadia; Bellotti, Vittorio; Arbustini, Eloisa; Perfetti, Vittorio; Ferrari, Marilyn E.; Zorzoli, Irene; Marinone, M G; Garini, Pietro

doi:10.1073/pnas.92.7.2959

Cited by 195 publications

(145 citation statements)

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“…However, in recent experiments, the incubation of Ab in the presence of Cu 21 resulted in decreased Ab fibril formation, although no explanation for these processes at the atomistic level has been provided. [11][12][13] Although several theoretical and experimental studies have been conducted with the aim of explaining the interaction of Cu 21 and Ab, several contradictory results have emerged. 16 These contradictions might be explained by the different experimental conditions used by different research groups, which have included different pH values, 23 21 , Ab suffered conformational changes.…”

Section: Discussionmentioning

confidence: 99%

“…7 In addition, numerous compounds have been found to reduce Ab 1242 aggregation in vitro. 11,12 However, the usefulness of these compounds as inhibitors of Ab 1242 aggregation remains speculative due to their lack of specificity and/or unknown mechanism of action. For example, galanthamine (Reminil V R ; AChE inhibitor) has been recently demonstrated to interact with soluble Ab to inhibit the formation of the toxic oligomeric species in a concentration-dependent manner, but its mechanism of interaction has not been well established.…”

Section: Introductionmentioning

confidence: 99%

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In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

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The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ1–42) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α‐helix to a β‐sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu2+ and various drugs used for AD treatment, such as galanthamine (Reminyl®), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu2+ and galanthamine prevent the formation of Aβ1–42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1–42 acquires a characteristic U‐shape before the α‐helix to β‐sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ1−42 in the presence of Cu2+ or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu2+) or to Lys 28 (galanthamine), which prevents Aβ1−42 from adopting the U‐characteristic conformation that allows the amino acids to transition to a β‐sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu2+ and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

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“…However the deposits are also rich in restricted subsets of heparan and dermatan sulphated glycosaminoglycans and proteoglycans, some of which are tightly but non-covalently associated with the ¢brils (Nelson & Pepys 1990). The role of glycosaminoglycans in amyloidogenesis is not known, but they may contribute to ¢brillogenesis by in£uencing protein folding and/or to ¢bril persistence by enhancing resistance to degradation.…”

Section: Amyloid Deposits Glycosaminoglycans and Serum Amyloid P Commentioning

confidence: 99%

“…Many groups and companies are active in this area, exploring small molecules, peptides and glycosaminoglycan analogues that bind to ¢bril precursors and stabilize their native fold, or interfere with refolding and/or aggregation into the cross-b core structure common to amyloid ¢brils, or bind to mature amyloid ¢brils and promote their refolding back towards the native conformation (Kisilevsky et al 1995;Merlini et al 1995;Peterson et al 1998;Soto 1999). Some of these agents are reported to interfere with experimental murine AA amyloidosis and we look forward to evaluating them in patients with systemic amyloidosis.…”

Section: (C) Inhibition Of ¢Brillogenesismentioning

confidence: 99%

Pathogenesis, diagnosis and treatment of systemic amyloidosis

Pepys

2001

Phil. Trans. R. Soc. Lond. B

203

156

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Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble ¢brils that disrupt tissue structure and cause disease. Although about 20 di¡erent unrelated proteins can form amyloid ¢brils in vivo, all such ¢brils share a common cross-b core structure. Some natural wild-type proteins are inherently amyloidogenic, form ¢brils and cause amyloidosis in old age or if present for long periods at abnormally high concentration. Other amyloidogenic proteins are acquired or inherited variants, containing amino-acid substitutions that render them unstable so that they populate partly unfolded states under physiological conditions, and these intermediates then aggregate in the stable amyloid fold. In addition to the ¢brils, amyloid deposits always contain the non-¢brillar pentraxin plasma protein, serum amyloid P component (SAP), because it undergoes speci¢c calcium-dependent binding to amyloid ¢brils. SAP contributes to amyloidogenesis, probably by stabilizing amyloid ¢brils and retarding their clearance. Radiolabelled SAP is an extremely useful, safe, speci¢c, non-invasive, quantitative tracer for scintigraphic imaging of systemic amyloid deposits. Its use has demonstrated that elimination of the supply of amyloid ¢bril precursor proteins leads to regression of amyloid deposits with clinical bene¢t. Current treatment of amyloidosis comprises careful maintenance of impaired organ function, replacement of end-stage organ failure by dialysis or transplantation, and vigorous e¡orts to control underlying conditions responsible for production of ¢bril precursors. New approaches under development include drugs for stabilization of the native fold of precursor proteins, inhibition of ¢brillogenesis, reversion of the amyloid to the native fold, and dissociation of SAP to accelerate amyloid ¢bril clearance in vivo.

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“…Furthermore fibrillogenic methods are important tools for designing compounds that, having the property to inhibit the fibril formation, may be candidates for new therapeutic strategies. An anti-fibrillogenic effect was demonstrated for certain sulfonate compounds [5], cyclodextrins [6], antibiotics [7] and peptides [S]. mAbs against the AD peptide (responsible for Alzheimer disease) have shown a strong and selective anti-fibrillogenic property [9].…”

mentioning

confidence: 99%

Use of Anti‐(β2 Microglobulin) mAb to Study Formation of Amyloid Fibrils

Stoppini

Bellotti

Mangione

et al. 1997

European Journal of Biochemistry

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Three mAbs, IgG,k 1F11, 7B6 and 14H3, were raised against in vitro-self-aggregated &Z-microglobulin. They recognize the native and unfolded forms of the protein and bind its fibrillar form that is present in amyloid tissue. When assayed in fibrillogenesis tests in vitro, mAb 14H3 inhibited fibril formation from m-microglobulin. This mAb recognizes a sequential epitope corresponding to the C-terminal octapeptide, residues 92-99, of /32-microglobulin. By using synthetic peptides it has been found that the integrity of the sequence is essential for the formation of the immunocomplex : the binding affinity is lowered by one order of magnitude (Kd from lo-' M to M) by removal of Met99 and completely abolished when both Asp98 and Met99 are lost or Arg98 is substituted with Lys. The other two mAbs, IF11 and 7B6, which bind sequences 20-41 and 63-75, respectively, are without effect on P;?-microglobulin fibrillogenesis. These two mAbs recognize p-microglobulin bound to the heavy chain in the major histocompatibility complex of type I located in the cell membrane, a property which is not shared by mAb 14H3.

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Interaction of the anthracycline 4'-iodo-4'-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis.

Cited by 195 publications

References 20 publications

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

Pathogenesis, diagnosis and treatment of systemic amyloidosis

Use of Anti‐(β2 Microglobulin) mAb to Study Formation of Amyloid Fibrils

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Interaction of the anthracycline 4'-iodo-4'-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis.

Cited by 195 publications

References 20 publications

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

Pathogenesis, diagnosis and treatment of systemic amyloidosis

Use of Anti‐(β2 Microglobulin) mAb to Study Formation of Amyloid Fibrils

Contact Info

Product

Resources

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In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process