Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

Pierfausto Seneci

• Publisher: Academic Press
• Year: 2015
• Print ISBN: 9780128019443
• eBook ISBN: 9780128019597
• Topic: Medicine
• Subtopic: Neurology

This book is a neurochemistry-based companion for Protein Misfolding and Neurodegenerative Diseases: Molecular Targets, an Elsevier title by the same author publishing in December 2014. While the first book focuses on biology and molecular targets, this companion book describes how these targets are regulated by small molecules and disease-modifying compounds. The book begins with a brief introduction to how key proteins become dysfunctional, and each subsequent chapter describes major disease mechanisms in Alzheimer's and other tauopathies. Properties and development status of these molecular targets and disease mechanisms are thoroughly described, as are small molecule effectors of autophagy and dis-aggregating agents. - Written to provide comprehensive coverage of neurodegenerative disease-modifying compounds - Provides discipline-specific chapters that cover medicinal chemistry and clinical applications - Provides an overview of more than 200 chemical classes and lead compounds, acting on selected molecular targets that are of relevance to any neurodegenerative disorder - Coverage of misfolding diseases, chaperone proteins, ubiquitination and autophagy/oncology makes this book suitable for structural neurochemists, chemists, biologists, non-CNS scientists, and scientists interested in drug discovery

Chapter 1

Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau

What is not Covered Next

Abstract

This chapter covers a small number of putative disease-modifying compounds, acting either on tau or on amyloid β (Aβ). Their mechanism of action is either unknown or different from the extensively exemplified mechanisms of the compounds described in Chapters 2 to 6. Namely, the structure and biological properties of six modulators of tau post-translational modifications (PTMs, phosphorylation and glycosylation), and of stabilizers of the structure of microtubules (MTs), are reported as putative tau pathology modifiers. Three γ-secretase inhibitors (GSI) and modulators (GSM), and three neuroprotective-proneurogenic compounds acting on Aβ peptides are also described. Their clinical characterization in studies on neurodegenerative disease (NDD) patients is thoroughly illustrated, as is the current status of research on each clinical candidate and on its analogues.

Keywords

small molecules

tau

microtubules

kinases

O-GlcNAcylation

β amyloid

γ-secretase inhibitors and modulators

proneurogenic compounds

Is this book comprehensive? I guess not. This is how the biology-oriented companion book [1] ends, and this is even truer at the end of this book. Here my task apparently was easier, as I planned to cover five pathways (chaperones (HSPs)/Chapter 2, ubiquitin proteasome system (UPS)/Chapter 3, autophagy/Chapter 4, aggrephagy/Chapter 5, anti-aggregation and disassembly of amyloidogenic proteins/Chapter 6) through the modulators of selected targets for each pathway (heat shock protein 27/Hsp27, Hsp70, Hsp90/Chapter 2; C-terminus of Hsc70 interacting protein/CHIP, ubiquitin-specific protease 14/USP14/Chapter 3; mammalian target of rapamycin complex 1/mTORC1/Chapter 4; p62, histone deacetylase 6/HDAC6/Chapter 5; tau antiaggregation and disassembly agents/Chapter 6). More than 250 compounds act on a mix of chemically validated (e.g., Hsp90, mTORC1, and tau aggregation inhibitors) and scarcely exploited targets (e.g., Hsp27, p62, and tau disassembly modulators). While writing the last words of Chapter 6, though, I realized that some well-characterized, putative disease-modifying compounds endowed with validated mechan...

Table of contents

• Cover
• Title page
• Table of Contents
• Copyright
• Dedication
• Abbreviations
• Chapter 1: Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau
• Chapter 2: Targeting the Protein Quality Control (PQC) Machinery
• Chapter 3: Targeting Proteasomal Degradation of Soluble, Misfolded Proteins
• Chapter 4: Targeting Unselective Autophagy of Cellular Aggregates
• Chapter 5: Targeting Selective Autophagy of Insoluble Protein Aggregates
• Chapter 6: Targeting Assembly and Disassembly of Protein Aggregates
• Index