Amyloid Beta: New Rational Structure-Based Therapeutic Development

Dear Colleagues,

The growing incidence of Alzheimer's disease (AD) in the general population worldwide is accompanied by an equivalent expected economic cost increase of 85% in 2030, making it a burden with the most significant economic impact on the national health system and social communities throughout the entire planet. In addition to the economic costs, the disease reduces the quality of life for those who suffer from it and those who associate with them. Scientific and clinical research on dementia is still exploring new therapeutic strategies and solving most problems through effective and inexpensive interventions.

According to the AD drug development pipeline report of 2021, 61% of the agents in phase 3 clinical trials of AD therapies and 86% in phase 2 are compounds that intend to achieve disease modification, with one-third having beta-amyloid or tau as the primary target, thus confirming that disease-modifying therapies based on amyloid hypothesis remain the principal approach for the treatment of AD. Until now, not all the failed clinical programs provided unquestionable proof of the amyloid hypothesis, and three main critical issues for amyloid-targeted therapies appeared:

i) The lack of deep knowledge of what in the pathogenic form of amyloid should be inhibited or removed to stop the disease progression;
ii) The importance of a correct brain concentration of the therapeutic agent, which is sufficient to elicit the desired biological response;
iii) The need for adequate diagnostic tools that enable the optimal study population to be enrolled in terms of relevance and the stage of the disease that best assesses efficacy.

Structure-based therapeutics have a relevant role in treating neurodegenerative diseases, particularly when the main challenge involves modulating large and relatively flexible surface areas typically found in protein–protein interactions. Research in this field has been oriented toward peptides because they offer many advantages, such as greater efficacy, specificity, and selectivity, owing to their intermediate size between small molecule drugs and protein therapeutics. Over the past decade, foldamers have increasingly attracted attention as favorable tools to mimic secondary structures of the peptides. In this regard, peptidomimetic foldamers represent a pharmacologically important class of compounds, as they are inspired by the structural features of their bioactive peptide counterparts.

In this Special Issue entitled “Amyloid Beta: New Rational Structure-Based Therapeutic Development”, we wish to focus on the design, synthesis, and application of new rational structure-based modulators of amyloid beta for successful therapies against neurodegenerative diseases. Research articles, comprehensive reviews, and short communications are welcome to collect the most recent insights and results in therapeutic innovation involving multidisciplinary approaches and addressing various pharmacological issues.

Dr. Nicolo Tonali
Dr. Lidia Ciccone
Guest Editors

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• amyloid beta
• Alzheimer’s disease
• foldamers
• structure-based therapeutics
• neurodegeneration
• secondary structure
• peptidomimetics
• protein–protein interactions
• molecular modelling
• biophysical analysis