Strategies Employing Transition Metal Complexes To Modulate

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Strategies Employing Transition Metal Complexes To Modulate Amyloid‑β Aggregation Jong-Min Suh,†,‡ Gunhee Kim,†,‡ Juhye Kang,†,§ and Mi Hee Lim*,† †

Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea

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ABSTRACT: Aggregation of amyloid-β (Aβ) peptides is implicated in the development of Alzheimer’s disease (AD), the most common type of dementia. Thus, numerous efforts to identify chemical tactics to control the aggregation pathways of Aβ peptides have been made. Among them, transition metal complexes as a class of chemical modulators against Aβ aggregation have been designed and utilized. Transition metal complexes are able to carry out a variety of chemistry with Aβ peptides (e.g., coordination chemistry and oxidative and proteolytic reactions for peptide modifications) based on their tunable characteristics, including the oxidation state of and coordination geometry around the metal center. This Viewpoint illustrates three strategies employing transition metal complexes toward modulation of Aβ aggregation pathways (i.e., oxidation and hydrolysis of Aβ as well as coordination to Aβ), along with some examples of such transition metal complexes. In addition, proposed mechanisms for three reactivities of transition metal complexes with Aβ peptides are discussed. Our greater understanding of how transition metal complexes have been engineered and used for alteration of Aβ aggregation could provide insight into the new discovery of chemical reagents against Aβ peptides found in AD.

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proceeds to generate protofibrils and fibrils through the elongation phase as well as mature fibrils at the plateau phase.11 The generated aggregates, including oligomers and fibrils, are reported to cause toxicity. Structured Aβ oligomers could induce toxicity toward neuronal cells through multiple routes: (i) disruptions of membrane microenvironments via interactions with lipid rafts and membrane-bound synaptic receptors; (ii) interruption of electrophysiological signaling especially in the synapse; (iii) dyshomeostasis of metal ions in the brain by generation of membrane-soluble channels.4,5,8 In addition to oligomers, Aβ fibrils are also shown to be involved in toxicity through breakage of neuronal branches with subsequent local synaptic abnormalities.12 Therefore, to control the toxicity triggered by Aβ aggregates (e.g., oligomers and fibrils), chemical approaches to inhibit Aβ aggregation would be necessary. Recently, transition metal complexes have been developed as chemical reagents capable of altering Aβ aggregation.13−26 In general, transition metal complexes have tunable properties, including oxidation and spin states of the metal center as well as their coordination geometries through a change in the ligands bound to the metal center.13−15,18,20,27−31 These variable characteristics could lead to the reactivity of transition metal complexes with Aβ species with consequent modulation of Aβ aggregation pathways. This Viewpoint briefly

INTRODUCTION Currently, ca. 47 million people worldwide are affected by Alzheimer’s disease (AD), a progressive neurodegenerative disease, and the number of patients is expected to reach ca. 75 million by 2030.1,2 Unfortunately, because of the complexity of the disease, the etiology of AD is still unclear. Among the hypotheses regarding the pathogenesis of AD, the amyloid cascade hypothesis, first proposed by Hardy and Higgins, claims that amyloid-β (Aβ) aggregates are neurotoxic, leading to the disease.3 Aβ peptides are produced via the proteolytic cleavage of amyloid precursor protein (APP) by β- and γsecretases.2,4−6 Two major isoforms of Aβ are Aβ40 (ca. 80− 90%) and Aβ42 (ca. 5−10%); their amino acid sequences are shown in Figure 1a.5,6 When Aβ monomers are transformed from random coil to a partially folded structure with an α-helix and a β-strand, they can interact with other folded monomers, which can produce aggregates, such as oligomers and fibrils.7−10 A major driving force for Aβ aggregation is hydrophobic interactions among peptides, mainly at the selfrecognition site (from Leu17 to Ala21) and hydrophobic Cterminal region (Figure 1a).2,9 As depicted in Figure 1b, the aggregation of Aβ occurs via a sigmoidal route, which is composed of three phases, i.e., lag, elongation, and plateau.9,11 At the initial stage (lag phase, also named nucleation), intrinsically disordered Aβ monomers become partially folded and are assembled with structured oligomers (called nuclei), which allow the progression of Aβ aggregation.9 Upon formation of the nuclei, Aβ aggregation © XXXX American Chemical Society

Received: October 3, 2018

A

DOI: 10.1021/acs.inorgchem.8b02813 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

summarizes three strategies employing transition metal complexes for modification of Aβ aggregation pathways (i.e., oxidative modification and hydrolytic cleavage of Aβ as well as coordination to Aβ; Figure 1c), along with some examples of such transition metal complexes (Table 1).

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STRATEGIES EMPLOYING TRANSITION METAL COMPLEXES TO CONTROL Aβ AGGREGATION Oxidation of Aβ Peptides. Oxidation of multiple amino acid residues in Aβ, such as His and Met, has been reported under oxidative stress [e.g., the presence of reactive oxygen species (ROS), such as singlet dioxygen (1O2), superoxide radical anion (O2•−), hydroxyl radical (•OH), and hydrogen peroxide (H2O2)].32 In particular, Met is especially vulnerable to oxidative reactions; thus, the role of its oxidation in biological systems has been actively investigated.33−36 Notably, the oxidation of Met35 has been shown to affect the aggregation of Aβ.37−41 When the Met35 residue in Aβ (Figure 1a) is oxidized via two-electron oxidation, forming the hydrophilic Met sulfoxide, the electronic property of Aβ peptides can be varied (e.g., enhancement of Aβ’s polarity), which could interrupt their hydrophobic interactions, crucial for the initiation and progression of Aβ aggregation.37,39,41 In addition to the Met35 residue, oxidation of the His residues in Aβ (i.e., His6, His13, and His14; Figure 1a) to 2oxohistidine(s) could influence Aβ aggregation pathways.13,32,42,43 The His residues in Aβ are associated with intramolecular and intermolecular interactions, including electrostatic interaction, cation−π interaction, π−π stacking, and hydrogen bonding.13,42,43 Such interactions are important for formation of partially folded monomers and aggregates. Therefore, upon modification of the Met and His residues in Aβ, Aβ aggregation can be changed.

Figure 1. Aggregation pathways of Aβ peptides and three approaches employing transition metal complexes for modulation of Aβ aggregation. (a) Amino acid sequences of Aβ40 and Aβ42. The selfrecognition site (LVFFA) is highlighted in bold and underlined. (b) Schematic representation of on-pathway Aβ aggregation. A sigmoidal curve of on-pathway Aβ aggregation is divided into three phases: lag, elongation, and plateau. (c) Three strategies to control Aβ aggregation by transition metal complexes, as illustrated in this Viewpoint: oxidation and hydrolysis of Aβ as well as coordination to Aβ.

Table 1. Summary of Transition Metal Complexes, Described in This Viewpoint, To Modulate Aβ Aggregation metal complexa

metal center

strategy

action sites

1

Ir(III)

oxidation

2 3 4 5

Ru(III) V(V) V(V) Co(III)

oxidation oxidation oxidation hydrolysis

His13, His14, Met35 n.d.b Met35 Met35 amide bond

6 7 8 9 10

Co(II) Pt(II) Pt(II) Pt(II) Pt(II), Ru(II) Rh(III) Co(III)

hydrolysis coordination coordination coordination coordination coordination coordination

11 12

technique to confirm the design strategy and modulating ability toward Aβ aggregationc

cytotoxicity experiments

ref

ESI-MS, NMR, gel/Western blot, TEM

X

13

O O O X

14 15 15 16

amide bond His6, His14 n.d.b n.d.b n.d.b

MALDI-MS, ThT assay, AFM, DLS ESI-MS, NMR, ThT assay, AFM, DLS ESI-MS, NMR, ThT assay, AFM, DLS MALDI-MS, quantitative measurement of Aβ species by filtration (30 kDa), compared to complex-free Aβ42, analyzed by gel/Western blot with an anti-soluble Aβ oligomer antibody (NU2) and silver staining. Upon enhancement of 12’s concentration, the population of oligomers (30 kDa) were more observed.21 Moreover, the resultant Aβ42 aggregates produced by addition of 12 showed lower synaptic binding to hippocampal neurons than complexuntreated Aβ42 species.21 These results suggested the potential ability of 12 to lower the toxicity mediated by Aβ42 oligomers because it was reported that the synaptic binding of oligomers could induce neurotoxicity.8,71

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SUMMARY AND OUTLOOK Aggregation of Aβ peptides is portrayed as a pathogenic feature in AD. Modulation of Aβ aggregation pathways generating less toxic Aβ aggregates is a promising tactic to diminish Aβinduced toxicity. As efforts, transition metal complexes have been developed as chemical modulators toward Aβ aggregation. This Viewpoint illustrates three strategies, i.e., (i) oxidation and (ii) hydrolysis of Aβ and (iii) coordination to F

DOI: 10.1021/acs.inorgchem.8b02813 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry biocompatibility would be critical. The chemistry (i.e., oxidation, hydrolysis, and coordination), mainly introduced in this Viewpoint, could occur with other biomolecules (e.g., other proteins, DNA, RNA, and lipids) over Aβ peptides. The unexpected oxidation and hydrolytic cleavage of biomolecules upon treatment with transition metal complexes, along with their nonspecific coordination, could trigger toxicity. Thus, the rational design of transition metal complexes with specificity toward Aβ would be valuable. For biocompatibility, several properties of transition metal complexes, such as BBB permeability, solubility in aqueous media, and metabolic stability, should be determined and evaluated. Because the aggregation pathway of Aβ includes three different phases, i.e., lag, elongation, and plateau (Figure 1b), it would be valuable to investigate the regulation of each aggregation phase by transition metal complexes designed by three strategies for future studies. Furthermore, the identification of metal complexes’ properties toward Aβ would be essential for optimization or new construction; thus, it should be accompanied by the development of proper biophysical techniques for that purpose. Overall, valuable efforts on searching and establishing the strategies for engineering novel biologically applicable transition metal complexes as chemical tools and potential therapeutics toward degenerative diseases (particularly, AD) have been made and are currently continued. The aggregation pathways of amyloidogenic peptides, including Aβ and islet amyloid polypeptide, could be affected by biomolecules, such as lipid membrane; thus, such interactions would be critical to consider for newly designing transition metal complexes for amyloidogenic peptide aggregation control.72−74

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amyloidogenic peptides found in the brains of neurodegenerative diseases.

Gunhee Kim obtained his B.S. degree in 2018 from the Department of Chemistry at UNIST, Ulsan, Republic of Korea. He is currently a graduate student in the group of Professor Mi Hee Lim at KAIST. His research interests lie in the development of chemical reagents that are able to regulate the activities of metal-free and metal-bound amyloidogenic peptides found in the brains of human neurodegenerative disorders.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Mi Hee Lim: 0000-0003-3377-4996 Author Contributions ‡

These authors contributed equally.

Juhye Kang is a doctoral student as a Global Ph.D. Fellow from the National Research Foundation of Korea (NRF) in the Department of Chemistry at UNIST, Ulsan, Republic of Korea, under the guidance of Professor Mi Hee Lim. She received her M.Sc. degree in 2014 in Chemistry from Seoul National University of Science and Technology, Seoul, Republic of Korea, under the supervision of Professor Cheal Kim. Her current research interests include the design of chemical tools that are capable of targeting amyloidogenic peptides and altering their aggregation and toxicity.

Notes

The authors declare no competing financial interest. Biographies

Jong-Min Suh received his B.S. degree in 2018 from the Department of Chemistry at UNIST, Ulsan, Republic of Korea. He is currently a graduate student in the laboratory of Professor Mi Hee Lim at KAIST. His recent research focuses on the development of transition metal complexes capable of controlling the aggregation pathways of G

DOI: 10.1021/acs.inorgchem.8b02813 Inorg. Chem. XXXX, XXX, XXX−XXX

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Mi Hee Lim is an Associate Professor in the Department of Chemistry at KAIST. In 2001, Professor Lim obtained her M.Sc. under Professor Wonwoo Nam at Ewha Womans University, Seoul, Republic of Korea. Professor Lim moved to Massachusetts Institute of Technology, Cambridge, MA, in 2002 where she received her Ph.D. under the supervision of Professor Stephen J. Lippard. She then pursued her postdoctoral research as a TRDRP postdoctoral fellow in the laboratory of Professor Jacqueline K. Barton at California Institute of Technology, Pasadena, CA. In the Summer of 2008, she began her independent career as an Assistant Professor of Chemistry and Research Assistant Professor in the Life Sciences Institute at the University of Michigan, Ann Arbor, MI. In the Fall of 2013, Professor Lim moved to UNIST, Ulsan, Republic of Korea, as an Associate Professor with tenure. Very recently, Professor Lim joined the Department of Chemistry at KAIST as an Associate Professor with tenure. Her current research interests lie in elucidating the individual and mutual roles of metals, proteins, oxidative stress, and inflammation in human diseases.

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ACKNOWLEDGMENTS The authors are thankful for the National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF-2016R1A5A1009405 and NRF-2017R1A2B3002585) and thank KAIST for support. J.K. also acknowledges the Global Ph.D. fellowship program for support through the NRF funded by the Ministry of Education (NRF2015HIA2A1030823).

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DOI: 10.1021/acs.inorgchem.8b02813 Inorg. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.inorgchem.8b02813 Inorg. Chem. XXXX, XXX, XXX−XXX