Design of β-Amyloid Aggregation Inhibitors from a Predicted Structural Motif

Novick, Paul; Lopes, Dahabada H. J.; Branson, Kristin; Esteras-Chopo, Alexandra; Graef, Isabella A.; Bitan, Gal; Pande, Vijay S.

doi:10.1021/jm201332p

Cited by 53 publications

(36 citation statements)

References 30 publications

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“…The Pande's compound was designed as follows. Ligand-based drug design was performed using the structure of Ab42Nle35p37 monomer, the top 100 best hits from the Maybrige Screening were tested in a single ThT aggregation assay and a compound was identified with effects on inhibition similar to the modified Ab1-42 peptide with an IC50 of 13 mM [29]. Arai performed rational design of a non-peptidic inhibitor (compound 17) based on the Ab16-20 pharmacophore under the assumption that intermolecular side chain and main chain interactions must be optimal and minimal, respectively [30 ].…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of protein aggregation and amyloid formation by small molecules

Doig

Derreumaux

2015

Current Opinion in Structural Biology

272

209

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Section: Discussionmentioning

confidence: 99%

“…Both peptides reduce Ab1-42 and TTR aggregation and toxicity at molar ratio of at least 10:1, but crossing BBB is highly unlikely [28]. Pande [29] and Arai [30 ] also designed two compounds.…”

Section: Other Moleculesmentioning

confidence: 99%

Inhibition of protein aggregation and amyloid formation by small molecules

Doig

Derreumaux

2015

Current Opinion in Structural Biology

272

209

View full text Add to dashboard Cite

“…The actions of the KP peptides in the neuronal cell systems do not appear to be mediated via activation of either the GPR-54 or NPFF receptor systems that are known targets of KP. 6,7,10,11 Compounds that bind to amyloid peptides are also likely to modify Congo red binding, 54 and the KP peptides shared this property. Congo red binding is suggestive of fibril formation, 19 and the ability of KP peptides to inhibit this suggests that there is potential inhibition of amyloid aggregation.…”

Section: ■ Conclusionmentioning

confidence: 99%

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

Milton

Chilumuri

Rocha‐Ferreira

et al. 2012

ACS Chem. Neurosci.

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Alzheimer's disease (AD) onset is associated with changes in hypothalamic-pituitary−gonadal (HPG) function. The 54 amino acid kisspeptin (KP) peptide regulates the HPG axis and alters antioxidant enzyme expression. The Alzheimer's amyloid-β (Aβ) is neurotoxic, and this action can be prevented by the antioxidant enzyme catalase. Here, we examined the effects of KP peptides on the neurotoxicity of Aβ, prion protein (PrP), and amylin (IAPP) peptides. The Aβ, PrP, and IAPP peptides stimulated the release of KP and KP 45−54. The KP peptides inhibited the neurotoxicity of Aβ, PrP, and IAPP peptides, via an action that could not be blocked by kisspeptin-receptor (GPR-54) or neuropeptide FF (NPFF) receptor antagonists. Knockdown of KiSS-1 gene, which encodes the KP peptides, in human neuronal SH-SY5Y cells with siRNA enhanced the toxicity of amyloid peptides, while KiSS-1 overexpression was neuroprotective. A comparison of the catalase and KP sequences identified a similarity between KP residues 42−51 and the region of catalase that binds Aβ. The KP peptides containing residues 45−50 bound Aβ, PrP, and IAPP, inhibited Congo red binding, and were neuroprotective. These results suggest that KP peptides are neuroprotective against Aβ, IAPP, and PrP peptides via a receptor independent action involving direct binding to the amyloid peptides. KEYWORDS: KiSS-1, kisspeptin, amyloid-β, prion protein, amylin, neuroprotection N euroendocrine hormone changes are seen in aging, and there are disease specific changes associated with Alzheimer's disease (AD). 1,2 One of the neuroendocrine systems to show profound changes with aging is the hypothalamic−pituitary−gonadal (HPG) system, and the pathology of AD, Creutzfeldt−Jakob disease (CJD), and type 2 diabetes mellitus (T2DM) is also associated with changes in the hormones of this system. 3,4 A major regulator of the HPGaxis is the 54 amino acid kisspeptin (KP) peptide, which acts on gonadotrophin-releasing hormone (GnRH) neurons to activate GnRH release. 5 The KP peptide is produced in neurons by processing of the KiSS-1 preproprotein to yield the 54 amino acid KP peptide, which corresponds to residues 68−121 of KiSS-1. 6 Shorter derivatives of KP peptide comprising the C-terminal 14 (KP 41−54), 13 (KP 42−54), and 10 (KP 45−54) amino acids have also been found in tissues and corresponding to residues 108− 121, 109−121, and 112−121 of KiSS-1. 6,7 Biological activity of KP peptides requires the KP 45−54 sequence and is mediated via a specific KP receptor (GPR-54). 6,7 Lack of KP signaling via the GPR-54 receptor is associated with reproductive system failure. 8 Cleavage of the KP 45−54 peptide between residues 51 and 52 by matrix metalloproteinases abolishes the activation of GPR-54 by the KP 45−54 peptide. 9 The KP 42−54 and KP 45−54 peptides also activate NPFF receptors, 10,11 and some of the actions of KP peptides could be mediated by NPFF receptor activation.There are profound changes in KP signaling at menopause 12 and notable sex differences in hypothalamic neurodegenera...

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“…Specifically, Molecular Dynamics (MD) has been recently employed in the emerging field of metallo-proteins and protein-metal interactions [34,35]. In the case of the Aβ peptide, MD results have been employed not only to guide experiments, but have also been instrumental in designing potential Aβ aggregation inhibitors [36,37].…”

Section: Introductionmentioning

confidence: 99%