Multivalent &amp; Multifunctional Ligands to &amp;#946;-Amyloid

Kim, Young Soo; Lee, Jihoon; Ryu, Ji-Yeon; Kim, Dong Jin

doi:10.2174/138161209787315648

Cited by 27 publications

(16 citation statements)

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“…Such strategies have been developed for the design of antimicrobial peptides as a means to treat bacterial infections (79) and for selective targeting of different amyloid-β (Aβ) species as a means to alleviate neurotoxicity (80). Our results suggest that the design of multivalent peptides can increase binding affinity, thus allowing these peptides to compete more effectively with other ligands in the cell.…”

Section: Discussionmentioning

confidence: 88%

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Posey

Ruff

Harmon

et al. 2018

Journal of Biological Chemistry

113

109

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Huntingtin N-terminal fragments (Htt-NTFs) with expanded polyglutamine tracts form a range of neurotoxic aggregates that are associated with Huntington's disease. Here, we show that aggregation of Htt-NTFs, irrespective of polyglutamine length, yields at least three phases (designated M, S, and F) that are delineated by sharp concentration thresholds and distinct aggregate sizes and morphologies. We find that monomers and oligomers make up the soluble M-phase, ~25 nm spheres dominate in the soluble S-phase, and long, linear fibrils make up the insoluble F-phase. Previous studies showed that profilin, an abundant cellular protein, reduces Htt-NTF aggregation and toxicity in cells. We confirm that profilin achieves its cellular effects through direct binding to the C-terminal proline-rich region of Htt-NTFs. We show that profilin preferentially binds to Htt-NTF M-phase species and destabilizes aggregation and phase separation by shifting the concentration boundaries for phase separation to higher values through a process known as polyphasic linkage. Our experiments, aided by coarse-grained computer simulations and theoretical analysis, suggest that preferential binding of profilin to the Mphase species of Htt-NTFs is enhanced through a combination of specific interactions between profilin and polyproline segments and auxiliary interactions between profilin and polyglutamine tracts. Polyphasic linkage may be a general strategy that cells utilize to regulate phase behavior of aggregation-prone proteins. Accordingly, detailed knowledge of phase behavior and an understanding of how ligands modulate phase boundaries may pave the way for developing new therapeutics against a variety of aggregation-prone proteins.Many diseases are associated with protein misfolding and aggregation (1,2). The aggregation process is often characterized by the presence of one or more threshold concentrations at which a sharp, discontinuous change to some aspect of the assembly state (e.g., size, conformational characteristics, material properties) occurs (3-6). Such a change can be described using the concepts of phase transitions. Phase separation, a subcategory of phase transitions, has recently received considerable attention due to increasing recognition of its importance in cell biology (7)(8)(9)(10)(11)(12)(13). Phase separation refers to aggregation-related changes in molecular density that give rise to the coexistence of dilute macromolecule-deficient phases and dense macromolecule-rich phases (3,14,15). Examples of multiple coexisting phases have been observed in biological contexts (15)(16)(17)(18), and these phases can be liquid, solid, or semisolid (e.g., a gel) (10,(19)(20)(21)(22)(23)(24)(25) Modulation of Htt-NTF aggregation via polyphasic linkage2 separation are quantified in terms of saturation concentrations (14,19,26). For a given two-phase system, the saturation concentration is the bulk concentration of the protein beyond which the solution separates into two coexisting phases. The lower the saturation concentration, t...

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Section: Discussionmentioning

confidence: 88%

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Posey

Ruff

Harmon

et al. 2018

Journal of Biological Chemistry

113

109

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“…Among recent possible treatments for ND, chelation therapy, or more conceptually correctly ''metal-targeted therapy'', are rapidly emerging as a promising and effective therapeutic option (see review Bolognin et al 2009;Hegde et al 2009;Kim et al 2009). The design of an effective metal-targeted therapy should necessarily take into account that metal dyshomeostasis associated with ND often does not correspond to a relevant overload of a specific metal but rather it is characterized by focal marked alterations of one or more metals in specific brain areas.…”

Section: Opportunities For Metal-targeted Treatments Of Ndmentioning

confidence: 99%

Metal Ion Physiopathology in Neurodegenerative Disorders

2009

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Metal dyshomeostasis in the brain (BMD) has often been proposed as a possible cause for several neurodegenerative disorders (NDs). Nevertheless, the precise nature of the biochemical mechanisms of metal involvement in NDs is still largely unknown. Mounting evidence suggests that normal aging itself is characterized by, among other features, a significant degree of metal ion dysmetabolism in the brain. This is probably the result of a progressive deterioration of the metal regulatory systems and, at least in some cases, of life-long metal exposure and brain accumulation. Although alterations of metal metabolism do occur to some extent in normal aging, they appear to be highly enhanced under various neuropathological conditions, causing increased oxidative stress and favoring abnormal metal-protein interactions. Intriguingly, despite the fact that most common NDs have a distinct etiological basis, they share striking similarities as they are all characterized by a documented brain metal impairment. This review will primarily focus on the alterations of metal homeostasis that are observed in normal aging and in Alzheimer's disease. We also present a brief survey on BMD in other NDs (Amyotrophic Lateral Sclerosis, Parkinson's, and Prion Protein disease) in order to highlight what represents the most reliable evidence supporting a crucial involvement of metals in neurodegeneration. The opportunities for metal-targeted pharmacological strategies in the major NDs are briefly outlined as well.

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“…In addition to AD treatment, it is also being evaluated as a potential agent in the treatment of dementia associated with depression [50]. The MTDL design strategy is an attractive approach for the development of anti-AD drugs, as attested by numerous research papers [51][52][53][54][55]. This review will focus on recent disclosures of dual or multifunctional compounds published between (approximately) 2008 and February 2011.…”

Section: Introductionmentioning

confidence: 99%

Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Bajda

Guzior²,

Ignasik³

et al. 2011

CMC

215

128

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Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H(3) receptor antagonism, cannabinoid CB(1) receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.

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Multivalent & Multifunctional Ligands to β-Amyloid

Cited by 27 publications

References 0 publications

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Metal Ion Physiopathology in Neurodegenerative Disorders

Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

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