A Copper-Binding Peptide with Therapeutic Potential against Alzheimer′s Disease: From the Blood–Brain Barrier to Metal Competition

López-Guerrero, Victor E.; Posadas, Yanahi; Sánchez-López, Carolina; Smart, Amanda; Miranda, Jael; Singewald, Kevin; Bandala, Yamir; Juaristi, Eusebio; Den Auwer, Christophe; Perez-Cruz, Claudia; González-Mariscal, Lorenza; Millhauser, Glenn; Segovia, Jose; Quintanar, Liliana

doi:10.1021/acschemneuro.4c00796

Title: A Copper-Binding Peptide with Therapeutic Potential against Alzheimer′s Disease: From the Blood–Brain Barrier to Metal Competition

Journal Article · 26 December 2024 · ACS Chemical Neuroscience

DOI: https://doi.org/10.1021/acschemneuro.4c00796 · OSTI ID:2483936

López-Guerrero, Victor E. ^[1];

^[1];

^[1]; Smart, Amanda ^[2]; Miranda, Jael ^[1]; Singewald, Kevin ^[2]; Bandala, Yamir ^[1];

^[3];

^[4];

^[1]; González-Mariscal, Lorenza ^[1];

^[2]; Segovia, Jose ^[1];

^[1]

Center for Research and Advanced Studies (Cinvestav), Mexico City (Mexico)
University of California, Santa Cruz, CA (United States)
Center for Research and Advanced Studies (Cinvestav), Mexico City (Mexico); El Colegio Nacional, Mexico City (Mexico)
Université Côte d′Azur, Nice (France)

Alzheimer’s disease (AD) is the most common form of dementia worldwide. AD brains are characterized by the accumulation of amyloid-β peptides (Aβ) that bind Cu²⁺ and have been associated with several neurotoxic mechanisms. Although the use of copper chelators to prevent the formation of Cu²⁺-Aβ complexes has been proposed as a therapeutic strategy, recent studies show that copper is an important neuromodulator that is essential for a neuroprotective mechanism mediated by Cu²⁺ binding to the cellular prion protein (PrPC). Therefore, in addition to metal selectivity and blood–brain barrier (BBB) permeability, an emerging challenge for copper chelators is to prevent the formation of neurotoxic Cu²⁺-Aβ species without perturbing the neuroprotective Cu²⁺-PrPC interaction. Previously, we reported the design of a tetrapeptide (TP) that withdraws Cu²⁺ from Aβ(1–16) and impacts the Cu²⁺-induced aggregation of Aβ(1–40). In this study, we improved the drug-like properties of TP in a BBB model, evaluated the metal selectivity of the optimized peptide (TP*), and tested its effect on Cu²⁺ coordination to PrPC and proteins involved in copper trafficking, such as copper transporter 1 and albumin. Our results show that changing the stereochemistry of the first residue prevents TP degradation in the BBB model and coadministration of TP with a peptide that increases BBB permeability allows its passage through the BBB model. TP* is highly selective toward Cu²⁺ in the presence of Zn²⁺ ions, transfers Cu²⁺ to copper-trafficking proteins, and forms a ternary TP*-Cu²⁺-PrP species that does not perturb the physiological conformation of PrP and displays only a minor impact in the neuroprotective Cu²⁺-dependent interaction of PrPC with the N-methyl-d-aspartate receptor. Overall, these results show that TP* displays desirable features for a copper chelator with therapeutic potential against AD. Moreover, this is the first study that explores the effect of a Cu²⁺ chelator with therapeutic potential for AD on Cu²⁺ coordination to PrPC (an emerging key player in AD pathology), integrating recent knowledge about metalloproteins involved in AD with the design of copper chelators against AD.

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Research Organization:: Center for Research and Advanced Studies (Cinvestav), Mexico City (Mexico)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2483936

Journal Information:: ACS Chemical Neuroscience, Journal Name: ACS Chemical Neuroscience Journal Issue: 2 Vol. 16; ISSN 1948-7193

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Alzheimer′s disease
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chelation therapy
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