A Cyclic Peptide Mimic of the β-Amyloid Binding Domain on Transthyretin

Cho, Patricia Y.; Joshi, Gururaj; Boersma, Melissa D.; Johnson, Jeffrey A.; Murphy, Regina M.

doi:10.1021/cn500272a

Cited by 23 publications

(50 citation statements)

References 39 publications

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“…[14] In this work we used human iPSC-derived neurons to detect cellular Aβ binding as a function of aggregation state, and to determine if cG8 and/or mTTR altered the cellular binding and internalization of Aβ. To do this, cells were treated with Aβ monomer, oligomer, or fibrils prepared alone or with cG8 or mTTR.…”

Section: Resultsmentioning

confidence: 99%

“…As described previously, our data are consistent with the hypothesis that binding of mTTR to oligomers completely arrests both the adoption of extended cross-β conformation and further self-assembly· [11d] The mechanism of action of cyclic peptides is similar, except that cyclic peptides also re-directs the self-association of a fraction of Aβ into large non-fibrillar amorphous clusters. [14] Although both mTTR and cG8 potently inhibit fibrillogenesis of Aβ, neither disaggregates preformed Aβ fibrils (Figure 4C,D). This is a favorable feature of an anti-Aβ compound if intermediate oligomeric aggregates are indeed the most toxic species.…”

Section: Discussionmentioning

confidence: 99%

“…[13] To increase peptide stability, we then created a cyclic peptide which showed greater inhibitory capability. [14] Further evolution produced cG8, which increased efficacy by increasing the adoption of an antiparallel β-strand structure and decreasing the tendency to self-associate. [15] …”

Section: Introductionmentioning

confidence: 99%

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Transthyretin Mimetics as Anti‐β‐Amyloid Agents: A Comparison of Peptide and Protein Approaches

et al. 2018

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β-Amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer’s disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-Aβ agents. We developed two compounds based on the Aβ-binding domain of transthyretin (TTR): a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α-synuclein. They both bind more Aβ aggregates than monomer, and neither disaggregates preformed fibrils. cG8 retained more of its activity in the presence of biological materials and was more resistant to proteolysis than mTTR. We examined the effect of mTTR or cG8 on Aβ binding to human neurons. When mTTR was co-incubated with Aβ under oligomer-forming conditions, Aβ morphology was drastically changed and Aβ-cell deposition significantly decreased. In contrast, cG8 did not affect morphology but decreased the amount of Aβ deposited. These results provide guidance for further evolution of TTR-mimetic anti-amyloid agents.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Transthyretin Mimetics as Anti‐β‐Amyloid Agents: A Comparison of Peptide and Protein Approaches

et al. 2018

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“…The cyclized 22-mer, CG3, proved to be more effective than the linear peptide at suppressing A β aggregation into fibrils, and at protecting neurons against A β toxicity (Figure 1). 35 …”

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confidence: 99%

TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides

Lū

Brickson

Murphy

2016

ACS Chem. Neurosci.

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β-Amyloid peptide (Aβ) self-associates into oligomers and fibrils, in a process that is believed to directly lead to neuronal death in Alzheimer’s disease. Compounds that bind to Aβ, and inhibit fibrillogenesis and neurotoxicity, are of interest as an anti-Alzheimer therapeutic strategy. Peptides are particularly attractive for this purpose, because they have advantages over small molecules in their ability to disrupt protein–protein interactions, yet they are amenable to tuning of their properties through chemical means, unlike antibodies. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to Aβ. We have taken a different approach, by designing Aβ-binding peptides using transthyretin (TTR) as a template. Previously, we demonstrated that a cyclic peptide, with sequence derived from the known Aβ-binding site on TTR, suppressed Aβ aggregation into fibrils and protected neurons against Aβ toxicity. Here, we searched for cyclic peptides with improved efficacy, by employing the algorithm TANGO, designed originally to identify amyloidogenic sequences in proteins. By using TANGO as a guide to predict the effect of sequence modifications on conformation and aggregation, we synthesized a significantly improved cyclic peptide. We demonstrate that the peptide, in binding to Aβ, redirects Aβ toward protease-sensitive, nonfibrillar aggregates. Cyclic peptides designed using this strategy have attractive solubility, specificity, and stability characteristics.

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“…TTR suppressed Aβ and prevent its toxicity [89] [90]. Studies showed that TTR sequestered Aβ in the CSF and J. Iqbal Journal of Behavioral and Brain Science moved Aβ to the choroid plexus (CP) for enzymatic degradation and removal from the brain [18].…”

Section: Ttr Role In Alzheimer Diseasementioning

confidence: 99%

Transthyretin—A Key Gene Involved in Regulating Learning and Memory in Brain, and Providing Neuroprotection in Alzheimer Disease via Neuronal Synthesis of Transthyretin Protein

Iqbal¹

2018

JBBS

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Transthyretin (TTR), a carrier protein present in the liver and choroid plexus of the brain, has been shown to be responsible for binding thyroid hormone thyroxin (T4) and retinol in plasma and cerebrospinal fluid (CSF). TTR aids in sequestering of beta-amyloid peptides Aβ deposition, and protects the brain from trauma, ischemic stroke and Alzheimer disease (AD). Accordingly, hippocampal gene expression of TTR plays a significant role in learning and memory as well as in simulation of spatial memory tasks. TTR via interacting with transcription factor CREB regulates this process and decreased expression leads to memory deficits. By different signaling pathways, like MAPK, AKT, and ERK via Src, TTR provides tropical support through megalin receptor by promoting neurite outgrowth and protecting the neurons from traumatic brain injury. TTR is also responsible for the transient rise in intracellular Ca 2+ via NMDA receptor, playing a dominant role under excitotoxic conditions. In this review, we tried to shed light on how TTR is involved in maintaining normal cognitive processes, its role in learning and memory, under memory deficit conditions; by which mechanisms it promotes neurite outgrowth; and how it protects the brain from Alzheimer disease (AD).

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A Cyclic Peptide Mimic of the β-Amyloid Binding Domain on Transthyretin

Cited by 23 publications

References 39 publications

Transthyretin Mimetics as Anti‐β‐Amyloid Agents: A Comparison of Peptide and Protein Approaches

Transthyretin Mimetics as Anti‐β‐Amyloid Agents: A Comparison of Peptide and Protein Approaches

TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides

Transthyretin—A Key Gene Involved in Regulating Learning and Memory in Brain, and Providing Neuroprotection in Alzheimer Disease via Neuronal Synthesis of Transthyretin Protein

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