A novel bis-furan scaffold for transthyretin stabilization and amyloid inhibition

Simões, Carlos J. V.; Almeida, Zaida L.; Costa, Dora C. S.; Jesus, Catarina S. H.; Cardoso, Ana L.; Almeida, Maria Rosário; Saraiva, Maria João; Melo, Teresa M. V. D. Pinho e; Brito, Rui M. M.

doi:10.1016/j.ejmech.2016.02.074

Cited by 18 publications

(11 citation statements)

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“…The association of drugs and biological ligands with lipid bilayers is a key step in their permeation through biological membranes, which is determinant for their disposition and availability at the target site. , There are several methods that may be used to characterize the association of biologically active molecules with, or their permeation through, biomembranes (see ref for a recent review). Among the available approaches, isothermal titration calorimetry (ITC) is particularly important, as it gives information on both the extent of association and the nature of the interactions established. − The methods available are however limited to ligands with intermediate to high partition coefficients and cannot be used for typical drugs and/or to characterize the association with very ordered lipid bilayers. − In the usual method used to obtain the association of small molecules with lipid bilayers, the lipid is added to an aqueous solution of the small molecule (solute). After injection i , the lipid concentration in the cell increases from that after the previous injection ([L] i −1 ) to [L] i , and this leads to an increase in the number of solute molecules that associate with the lipid bilayer from which heat q i is evolved, eq ,, where n S_L i –1 and n S_L i are the numbers of moles of solute associated with the lipid bilayer before and after injection i , respectively; Δ H ° is the molar enthalpy variation associated with the transfer of solute from the aqueous media to the lipid bilayer; V i and V cell are, respectively, the volume injected in each titration step and the volume of the cell; and q dil is the heat of diluting the concentrated lipid solution.…”

Section: Introductionmentioning

confidence: 99%

Partition of Amphiphilic Molecules to Lipid Bilayers by ITC: Low-Affinity Solutes

Samelo¹,

Mora

Granero

et al. 2017

ACS Omega

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A protocol is developed to allow the accurate characterization of partition to lipid bilayers for solutes with low affinity, using isothermal titration calorimetry. The methodology proposed is suitable for studies using complex membranes, such as intact biomembranes or whole cells. In the method developed, the association is characterized at increasing solute concentrations. This allows the characterization of solute partition into unperturbed membranes, as well as effects induced by high solute concentrations. Most druglike molecules are expected to interact with low-to-moderate affinity with relevant cell membranes. This is due to both the need for a relatively high aqueous solubility of the drug and the poor binding properties of the cell membranes. The methodology is applied to characterize the interaction of antibiotic Rifampicin with 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine and with lipid bilayers representative of bacterial membranes.

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Section: Introductionmentioning

confidence: 99%

Partition of Amphiphilic Molecules to Lipid Bilayers by ITC: Low-Affinity Solutes

Samelo¹,

Mora

Granero

et al. 2017

ACS Omega

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“…The fibril formation protocol at pH 4.4 is widely used for in vitro TTRwt amyloid fibrillogenesis inhibitor screening, as it is easily implemented in medium or high throughput screening formats in tubes or microwell plates, usually followed by turbidity measurements [ 56 , 57 , 58 ]. Thus, this protocol seems to be a very good candidate for use in TTRwt disaggregation assays.…”

Section: Discussionmentioning

confidence: 99%

Searching for the Best Transthyretin Aggregation Protocol to Study Amyloid Fibril Disruption

Ferreira

Almeida

Cruz

et al. 2021

IJMS

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Several degenerative amyloid diseases, with no fully effective treatment, affect millions of people worldwide. These pathologies—amyloidoses—are known to be associated with the formation of ordered protein aggregates and highly stable and insoluble amyloid fibrils, which are deposited in multiple tissues and organs. The disruption of preformed amyloid aggregates and fibrils is one possible therapeutic strategy against amyloidosis; however, only a few compounds have been identified as possible fibril disruptors in vivo to date. To properly identify chemical compounds as potential fibril disruptors, a reliable, fast, and economic screening protocol must be developed. For this purpose, three amyloid fibril formation protocols using transthyretin (TTR), a plasma protein involved in several amyloidoses, were studied using thioflavin-T fluorescence assays, circular dichroism (CD), turbidity, dynamic light scattering (DLS), and transmission electron microscopy (TEM), in order to characterize and select the most appropriate fibril formation protocol. Saturation transfer difference nuclear magnetic resonance spectroscopy (STD NMR) was successfully used to study the interaction of doxycycline, a known amyloid fibril disruptor, with preformed wild-type TTR (TTRwt) aggregates and fibrils. DLS and TEM were also used to characterize the effect of doxycycline on TTRwt amyloid species disaggregation. A comparison of the TTR amyloid morphology formed in different experimental conditions is also presented.

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“…Nevertheless, in our experiments, we observe that, for amyloidogenic variants, initial TTR oligomerization occurs via self-assembly of monomeric units at least up to octamers, prior to the formation of HMW aggregates, which occurs faster for TTRV30M and TTRL55P than for TTRwt, in agreement with the natural amyloidogenicity of these variants. Presently, therapeutic strategies and clinically approved drugs against TTR amyloidosis aim to stabilize the TTR tetramer [71,72] or suppress TTR production [73,74]. Nonetheless, other molecular species, such as monomers or LMW oligomers, can be seen as relevant therapeutic targets and may represent a viable alternative for drug development towards the inhibition of amyloid formation by TTR.…”

Section: Discussionmentioning

confidence: 99%

Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity

et al. 2020

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One of the molecular hallmarks of amyloidoses is ordered protein aggregation involving the initial formation of soluble protein oligomers that eventually grow into insoluble fibrils. The identification and characterization of molecular species critical for amyloid fibril formation and disease development have been the focus of intense analysis in the literature. Here, using photo-induced cross-linking of unmodified proteins (PICUP), we studied the early stages of oligomerization of human transthyretin (TTR), a plasma protein involved in amyloid diseases (ATTR amyloidosis) with multiple clinical manifestations. Upon comparison, the oligomerization processes of wild-type TTR (TTRwt) and several TTR variants (TTRV30M, TTRL55P, and TTRT119M) clearly show distinct oligomerization kinetics for the amyloidogenic variants but a similar oligomerization mechanism. The oligomerization kinetics of the TTR amyloidogenic variants under analysis showed a good correlation with their amyloidogenic potential, with the most amyloidogenic variants aggregating faster (TTRL55P > TTRV30M > TTRwt). Moreover, the early stage oligomerization mechanism for these variants involves stepwise addition of monomeric units to the growing oligomer. A completely different behavior was observed for the nonamyloidogenic TTRT119M variant, which does not form oligomers in the same acidic conditions and even for longer incubation times. Thorough characterization of the initial steps of TTR oligomerization is critical for better understanding the origin of ATTR cytotoxicity and developing novel therapeutic strategies for the treatment of ATTR amyloidosis.

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A novel bis-furan scaffold for transthyretin stabilization and amyloid inhibition

Cited by 18 publications

References 53 publications

Partition of Amphiphilic Molecules to Lipid Bilayers by ITC: Low-Affinity Solutes

Partition of Amphiphilic Molecules to Lipid Bilayers by ITC: Low-Affinity Solutes

Searching for the Best Transthyretin Aggregation Protocol to Study Amyloid Fibril Disruption

Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity

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