Editorial [ Therapeutics for Protein Misfolding Diseases Executive Editor: Claudio Soto ]

The appropriate functioning of living organisms depends upon the correct performance and inter-relationship of different organs and tissues. Cells are the basic units of tissues and their proper function depends upon a network of thousand of proteins, each of which plays an important and specific role. The biological function of a protein depends on its threedimensional structure, which is determined by its amino acid sequence during the process of protein folding. In spite that protein folding is a process carefully regulated to avoid and correct mistakes; in the last few years, it has become clear that diverse diseases are the result of protein misfolding. These diseases are now grouped together under the name of protein misfolding disorders (PMDs). This group includes Alzheimer's disease, transmissible spongiform encephalopathies, serpin-deficiency disorders, hemolytic anemia, Huntington disease, cystic fibrosis, diabetes type II, Amyotrophic Lateral Sclerosis, Parkinson disease, spinocerebellar ataxias, dialysis-related amyloidosis and more than 15 other less well-known diseases. The hallmark event in these diseases is the misfolding of an otherwise normal protein, which usually aggregates and accumulates in diverse tissues (Fig. 1), inducing cell death, tissue damage and organ dysfunction. This issue of Current Pharmaceutical Design contains 4 articles reviewing different approaches for therapy of these diseases. Some of the articles are focused in a particular disease, but the approaches described can be extrapolated to other members of the group. The first article by Herbst and Wanker [1] describes the identification and evaluation of small chemical molecules to inhibit misfolding and aggregation of poly-glutamine rich proteins, implicated in the pathogenesis of Huntington disease, spinocerebellar ataxias and other rare diseases. The authors also describe the possibility of inducing a heat-shock response to upregulate the concentration of molecular chaperon proteins that may interfere or correct the misfolding event. The second article by Estrada and Soto [2] reviews the use of short synthetic peptides rationally designed to interact specifically with the protein undergoing misfolding and prevents the conformational changes leading to the accumulation of misfolded aggregates. The peptide approach has been extensively used in several PMDs and some of the more developed compounds have reached clinical trials. The article by Sigurdsson [3] describes the immunotherapeutic approach for preventing misfolding and aggregation. This strategy is based on using the immune system, either by active or passive immunization to remove specifically the protein implicated in the different diseases. Much progress has been done in analyzing the effectiveness of the immunotherapy, mainly in Alzheimer' s disease and prion-related disorders. Finally, the article by Varela-Nallar, Gonzalez and Inestrosa [4] discusses the role of metal ions in protein misfolding, focusing specifically on prion diseases. Metal ions, and particularly copper, zinc and aluminum, have been extensively implicated in the process of protein misfolding and aggregation in several PMDs. Despite various therapeutic strategies have been designed to interfere with the binding of the metal ions to the misfolded protein, it is still not clear whether this interaction is beneficial or detrimental. The overall aim of these 4 articles is to discuss the strengths and limitations of different strategies used and the under development which interferes with protein misfolding and aggregation and possibility to use them as a novel treatment for a variety of diseases. References [1] Herbst M, Wanker EE. Therapeutic Approaches to Polyglutamine Diseases: Combating Protein Misfolding and Aggregation. Curr Pharm Design 2006; 12(20): 2543-2555. [2] Estrada LD, Soto C. Inhibition of Protein Misfolding and Aggregation by Small Rationally-Designed Peptides. Curr Pharm Design 2006; 12(20): 2557-2567. [3] Sigurdsson EM. Immunotherapy for Conformational Diseases. Curr Pharm Design 2006; 12(20): 2569-2585. [4] Varela-Nallar L, Gonzalez A, Inestrosa NC. Role of Copper in Prion Diseases: Deleterious or Beneficial. Curr Pharm Design 2006; 12(20): 2587-2595.