Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Saelices, Lorena; Chung, Kevin; Lee, Ji Hun; Coelho, Teresa; Bijzet, Johan; Benson, Merrill D.; Eisenberg, David

doi:10.1101/354720

Cited by 2 publications

(7 citation statements)

References 30 publications

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“…5C) and no significant effect on the disease-related locomotor decline (Fig. 2 and 3) (Saelices et al, 2018a).…”

Section: Resultsmentioning

confidence: 96%

“…Inhibition of TTR aggregation and amyloid seeding by peptide inhibitors may represent a novel strategy for halting progression of ATTR, especially for those cases where liver transplantation or stabilization by small compounds may not be sufficient (Saelices et al, 2018a; Saelices et al, 2018b). The peptide inhibitor TabFH1 was designed against the two amyloid-driving segments of TTR to target amyloid growth of existing TTR fibrils (Saelices et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…Purity and molecular weight were confirmed by MALDI-TOF and reversed phase HPLC. The sequences of our peptides are: TabFH1 is an equimolar cocktail of RRRRPFHEHA(N-methyl)EVVFTA and RRRRPYSYSTT(N-methyl)AVVTN; TabFH2 is an equimolar cocktail of RRRRHVAHPFV(N-methyl)EFTE and RRRRSYVTNPTSY(N-methyl)AVT, as previously described (Saelices et al, 2018a). All peptides were dissolved in 0.22 μm filtered water, first to 5 mM stock solution.…”

Section: Methodsmentioning

confidence: 99%

“…In two recent studies, we have developed and optimized peptide inhibitors that inhibit both transthyretin aggregation in vitro as well as amyloid seeding catalyzed by ATTR ex-vivo amyloid fibrils (Saelices et al, 2015; Saelices et al, 2018a; Saelices et al, 2018b). We first discovered that there are two amyloidogenic segments of TTR that drive protein aggregation: β-strands F and H (Saelices et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…In that study, we determined the atomic structures of these two segments in their amyloid form, which allowed us to design specific peptide inhibitors of F and H β-strands self-association. Later we further optimized these inhibitors to inhibit amyloid seeding driven by ATTR ex-vivo amyloid fibrils (Saelices et al, 2018a).…”

Section: Introductionmentioning

confidence: 99%

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Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR

Saelices

Pokrzywa²,

Pawelek³

et al. 2018

Neurobiology of Disease

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Transthyretin amyloidosis (ATTR) is a fatal disease caused by the systemic aggregation and deposition of transthyretin (TTR), a blood transporter that is mainly produced in the liver. TTR deposits are made of elongated amyloid fibrils that interfere with normal tissue function leading to organ failure. The current standard care for hereditary neuropathic ATTR is liver transplantation or stabilization of the native form of TTR by tafamidis. In our previous work, we explored an additional strategy to halt protein aggregation by capping pre-existing TTR fibrils with structure-based designed peptide inhibitors. Our best peptide inhibitor TabFH2 has shown to be effective at inhibiting not only TTR aggregation but also amyloid seeding driven by fibrils extracted from ATTR patients. Here we evaluate the effects of peptide inhibitors in two Drosophila models of neuropathic ATTR and compared their efficacy with diflunisal, a protein stabilizer currently used off-label for the treatment of ATTR. Our peptide inhibitor TabFH2 was found the most effective treatment, which resulted in motor improvement and the reduction of TTR deposition. Our in vivo study shows that inhibiting TTR deposition by peptide inhibitors may represent a therapeutic strategy for halting the progression of ATTR.

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“…5C) and no significant effect on the disease-related locomotor decline (Fig. 2 and 3) (Saelices et al, 2018a).…”

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR

Saelices

Pokrzywa²,

Pawelek³

et al. 2018

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

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Inhibition of Amyloid Aggregation and Toxicity with Janus Iron Oxide Nanoparticles

et al. 2021

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Amyloid aggregation is a ubiquitous form of protein misfolding underlying the pathologies of Alzheimer’s disease (AD), Parkinson’s disease (PD), and type 2 diabetes (T2D), three primary forms of human amyloid diseases. While much has been learned about the origin, diagnosis, and management of these neurological and metabolic disorders, no cure is currently available due in part to the dynamic and heterogeneous nature of the toxic oligomers induced by amyloid aggregation. Here, we synthesized β-casein-coated iron oxide nanoparticles (βCas IONPs) via a 2-(bis-((phosphonic acid)methyl)amino)ethyl-(poly(oligo ethylene glycol)methyl ether acrylate)-b-(poly(N-ethyl-2,3-dibromomaleimide)acrylate)-((butylthio)-carbonothioyl)thio propionate (BPA-P(OEGA-b-DBM)) block copolymer linker. Using a thioflavin T kinetic assay, transmission electron microscopy, Fourier transform infrared spectroscopy, discrete molecular dynamics simulations, and cell viability assays, we examined the Janus characteristics and the inhibition potential of βCas IONPs against the aggregation of amyloid β (Aβ), α synuclein (αS), and human islet amyloid polypeptide (IAPP), which are implicated in the pathologies of AD, PD, and T2D. Incubation of zebrafish embryos with the amyloid proteins largely inhibited hatching and elicited reactive oxygen species, which were effectively rescued by the inhibitor. Furthermore, Aβ-induced damage to the mouse brain was mitigated in vivo with the inhibitor. This study revealed the potential of Janus nanoparticles as a new nanomedicine against a diverse range of amyloid diseases.

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Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Cited by 2 publications

References 30 publications

Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR

Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR

Inhibition of Amyloid Aggregation and Toxicity with Janus Iron Oxide Nanoparticles

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