Pseudo-peptide amyloid-β blocking inhibitors: molecular dynamics and single molecule force spectroscopy study

Mehrazma, Banafsheh; Robinson, Morgan; Opare, Stanley; Petoyan, Anahit; Lou, Jennifer W.; Hane, Francis; Rauk, Arvi; Leonenko, Zoya

doi:10.1016/j.bbapap.2017.07.022

Cited by 16 publications

(16 citation statements)

References 70 publications

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“…As with the all- l -amino acid pseudo-peptides of the SGA and SGC series previously discussed [ 30 , 31 ], the all- d -pseudo-peptides, SGB1 and SGD1, form antiparallel and parallel β-sheet structures, respectively, when bound to R. There are two possibilities for either SGB1 or SGD1 to interact with the β-strand of R peptide. With the standard positioning of R, the pseudo-peptides can be introduced either on the top edge (T-edge) or on the bottom edge (B-edge) of R. The resulting structures are shown in Figure 2 and Figure 3 for R T -SGB1, R B -SGB1 and R T -SGD1, R B -SGD1, respectively.…”

Section: Results For Sgb1 Sgd1 Sgb1-r and Sgd1-rmentioning

confidence: 90%

“… a Aβ 42 numbering of R, natural numbering of the pseudo-peptides; b The average intermolecular hydrogen bond count from the first cluster in MD simulation; c The Effective ∆G eff = 2 ∆G R-PP − ∆G RR − ∆G PP-PP ; d,e These values were previously reported by Mehrazma et al [ 30 , 31 ]; f For the parallel β-sheets, the registry does not apply. …”

Section: Figurementioning

confidence: 78%

“…Previously, the interaction of R with the all- l -amino acid SGC1, with similar sequence as the all-D PP, SGD1, yielded ∆G eff RT-SGC1 = −27 kJ/mol and ∆G eff RB-SGD1 = −21 kJ/mol. [ 31 ] In the case of SGD1, the umbrella sampling calculations yielded ∆G eff RT-SGD1 = −15 kJ/mol and ∆G eff RB-SGD1 = −1 kJ/mol ( Table 1 ). These results suggest that that the retro-inverso all- d -amino acid SGD1 is not as effective at dissociating R as the related retro-inverso all- l -amino acid SGC1 at 1:1 stoichiometry.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we have studied four classes of pseudo-peptides that bind to R with high affinity: SGA, SGB, SGC, SGD [ 23 , 29 , 30 , 31 ]. The sequences of the selected pseudo-peptides in each group is as following: SGA3 = N -Acetyl-Daba1-Orn2-MeLeu3-Phe4-MePhe5-Leu6-Ala7-Glu8-NH 2 SGB1 = N -Acetyl-daba1-orn2-leu3-mephe4-phe5-mephe6-leu7-glu8-NH 2 SGC1 = N -Acetyl-Glu1-Ala2-MePhe3-Phe4-MePhe5-Leu6-Orn7-Daba8-NH 2 SGD1 = N -Acetyl-glu1-leu2-mephe3-phe4-mephe5-leu6-orn7-daba8-NH 2 where the lower case designates the d -amino acids and Daba = diaminobutyric acid, Orn = ornithine, MeLeu = N -methylleucine, MePhe = N -methylphenylalanine.…”

Section: Introductionmentioning

confidence: 99%

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d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors

et al. 2018

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A causative factor for neurotoxicity associated with Alzheimer’s disease is the aggregation of the amyloid-β (Aβ) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out to study the interaction of the pseudo-peptides with both Aβ13–23 (the core recognition site of Aβ) and full-length Aβ1–42. Umbrella sampling MD calculations have been used to estimate the free energy of binding, ∆G, of these peptides to Aβ13–23. The highest ∆Gbinding is found for SGB1. Each of the pseudo-peptides was also docked to Aβ1–42 and subjected up to seven microseconds of all atom molecular dynamics simulations. The resulting structures lend insight into how the dynamics of Aβ1–42 are altered by complexation with the pseudo-peptides and confirmed that SGB1 may be a better candidate for developing into a drug to prevent Alzheimer’s disease.

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Section: Results For Sgb1 Sgd1 Sgb1-r and Sgd1-rmentioning

confidence: 90%

Section: Figurementioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors

et al. 2018

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“…Moreover, atomic force microscopy, together with molecular dynamics simulations, has demonstrated that some pseudopeptides might bind to amyloid fragments with varying degrees of affinity to prevent Aβ–Aβ aggregation [ 98 ]. Similarly, the other β-sheet breaker peptides were designed to complement the enthalpic interactions with the aggregating protein to inhibit the pathological process in a concentration-dependent manner [ 99 ].…”

Section: Current and Novel Treatment Modalitiesmentioning

confidence: 99%

The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer’s Disease and Associated Amyloid Cardiomyopathy?

et al. 2021

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Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aβ pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain–ear–heart axis by which Aβ and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease.

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Molecular Dynamics Simulations on Drug Delivery Systems

Shariatinia‬

2021

Modeling and Control of Drug Delivery Systems

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Pseudo-peptide amyloid-β blocking inhibitors: molecular dynamics and single molecule force spectroscopy study

Cited by 16 publications

References 70 publications

d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors

d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors

The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer’s Disease and Associated Amyloid Cardiomyopathy?

Molecular Dynamics Simulations on Drug Delivery Systems

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