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The structural evolution of ?-secretase inhibitors: a focus on the development of small-molecule inhibitors.

ABSTRACT: Effective treatment of Alzheimer's disease (AD) remains a critical unmet need in medicine. The lack of useful treatment for AD led to an intense search for novel therapies based on the amyloid hypothesis, which states that amyloid ?-42 (A?42) plays an early and crucial role in all cases of AD. ?-Secretase (also known as BACE-1 ?-site APP-cleaving enzyme, Asp-2 or memapsin-2) is an aspartyl protease representing the rate limiting step in the generation of A? peptide fragments, therefore it could represent an important target in the steady hunt for a disease-modifying treatment. Generally, ?-secretase inhibitors are grouped into two families: peptidomimetic and nonpeptidomimetic inhibitors. However, irrespective of the class, serious challenges with respect to blood-brain barrier (BBB) penetration and selectivity still remain. Discovering a small molecule inhibitor of ?-secretase represents an unnerving challenge but, due to its significant potential as a therapeutic target, growing efforts in this task are evident from both academic and industrial laboratories. In this frame, the rising availability of crystal structures of ?-secretase-inhibitor complexes represents an invaluable opportunity for optimization. Nevertheless, beyond the inhibitory activity, the major issue of the current research approaches is about problems associated with BBB penetration and pharmacokinetic properties. This review follows the structural evolution of the early ?-secretase inhibitors and gives a snap-shot of the hottest chemical templates in the literature of the last five years, showing research progress in this field.

SUBMITTER: Butini S

PROVIDER: S-EPMC6034716 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The structural evolution of β-secretase inhibitors: a focus on the development of small-molecule inhibitors.

Butini Stefania S Brogi Simone S Novellino Ettore E Campiani Giuseppe G Ghosh Arun K AK Brindisi Margherita M Gemma Sandra S

Current topics in medicinal chemistry 20130101 15

Effective treatment of Alzheimer's disease (AD) remains a critical unmet need in medicine. The lack of useful treatment for AD led to an intense search for novel therapies based on the amyloid hypothesis, which states that amyloid β-42 (Aβ42) plays an early and crucial role in all cases of AD. β-Secretase (also known as BACE-1 β-site APP-cleaving enzyme, Asp-2 or memapsin-2) is an aspartyl protease representing the rate limiting step in the generation of Aβ peptide fragments, therefore it could ...[more]

PMID: 23931442

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Project description:Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the γ-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation toward the multiciliated lineage. Thus, γ-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here, we demonstrate the therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In summary, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases.NEW & NOTEWORTHY Our findings show that low-dose, short-term topical or systemic γ-secretase inhibitor treatment may lead to restoration of multiciliated cells without toxicity and potentially improve epithelial function in a wide range of chronic lung diseases.

Dataset Information

The structural evolution of ?-secretase inhibitors: a focus on the development of small-molecule inhibitors.

Publications

The structural evolution of β-secretase inhibitors: a focus on the development of small-molecule inhibitors.

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