Therapeutic approaches to protein-misfolding diseases

  title={Therapeutic approaches to protein-misfolding diseases},
  author={Fred E. Cohen and Jeffery W. Kelly},
Several sporadic and genetic diseases are caused by protein misfolding. These include cystic fibrosis and other devastating diseases of childhood as well as Alzheimer's, Parkinson's and other debilitating maladies of the elderly. A unified view of the molecular and cellular pathogenesis of these conditions has led to the search for chemical chaperones that can slow, arrest or revert disease progression. Molecules are now emerging that link our biophysical insights with our therapeutic… 
Therapeutic strategies against protein misfolding in neurodegenerative diseases
The knowledge of the mechanism of protein misfolding and aggregation, its role in neurodegeneration and the diverse therapeutic targets for intervention are described and various strategies under development to discover drugs attacking this process are reviewed.
Developing therapeutics for the diseases of protein misfolding
The prion diseases are illustrative of this group of misfolding disorders and provide a model system for therapeutic intervention and strategies to inhibit the replication and accumulation of the prion protein are being developed and have entered animal and clinical studies.
Cross currents in protein misfolding disorders: interactions and therapy.
A better knowledge of the molecular basis of PMDs could have important implications for understanding the mechanism by which these diseases appear and progress and ultimately to develop novel strategies for treatment.
Protein aggregation, misfolding and consequential human neurodegenerative diseases
The present review deals with the human neurodegenerative diseases caused due to the protein misfolding highlighting pathomechanisms and therapeutic intervention.
Protein‐misfolding diseases and chaperone‐based therapeutic approaches
Functional aspects of the different types of chaperones suggest their uses as potential therapeutic agents against different type of degenerative diseases, including neurodegenerative disorders.
Screening methods for identifying pharmacological chaperones.
This review highlights recent strategies for identifying small-molecules that act as pharmacological chaperones and revert protein misfolding diseases, with a focus on reports within the last five years.
Chemical Chaperone and Inhibitor Discovery: Potential Treatments for Protein Conformational Diseases
It is believed that a better understanding of the mechanisms of conformational changes as well as the biological functions of these proteins will lead to the development and design of potential interfering compounds against amyloid formation associated with protein conformational diseases.


Therapeutic strategies for human amyloid diseases
This review will look at small-molecule and macromolecular approaches for intervention in amyloid diseases other than Alzheimer's disease, although select examples from Alzheimer’s disease will be discussed.
Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics
A series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidsogenesis by stabilizing the native state.
Alpha1-antitrypsin deficiency--a model for conformational diseases.
This review article summarizes the action of these protease inhibitors and how mutations lead to their accumulation in particular neurodegenerative disorders such as prion encephalopathies and Alzheimer's disease.
Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease
It is proposed that NN-DNJ chaperones β-Glu folding at neutral pH allows the stabilized enzyme to transit from the endoplasmic reticulum to the Golgi, enabling proper trafficking to the lysosome.
β-Secretase (BACE) as a drug target for alzheimer’s disease
Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa*
Protein conformational disorders, which include certain types of retinitis pigmentosa, are a set of inherited human diseases in which mutant proteins are misfolded and often aggregated. Many opsin
Anti-aggregating antibodies, a new approach towards treatment of conformational diseases.
The immunological concept in the treatment of conformational diseases, and the recent performance of such antibodies in transgenic mice, as a model for human diseases, suggests the development of vaccination approaches against such diseases.
Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein.
Using NMR spectroscopy, the millimolar dissociation constant of the complex suggests that in vivo inhibition of prion propagation occurs after 10000-fold concentration of quinacrine within endolysosomes.
Therapeutic approaches to repair defects in deltaF508 CFTR folding and cellular targeting.