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Free Content Editorial [Hot Topic: A Role for Immunophilins in Cellular Signalling in Health and Disease (Guest Editors: Juan Antonio Rosado Dionisio and Pedro Cosme Redondo Liberal)]

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Abstract:

Tissue and organ transplantation constitute the main medical advances of the last century, and has been possible thanks to the contribution of doctors like Loix Roux, who, in 1885, firstly described a technique consisting on tissue culture ex vivo, or Emerich Ullman and Max Lederer, whose publications in 1914 collected all preliminary surgical advances in the field. These pioneers soon realized the need to avoid the interference of the immunological system in order to obtain successful allotropic organ transplantation.

At the beginning of the 80's, cyclosporin (CsA), previously isolated and characterized in 1969 from the fungus Tolypocladium inflatum, became a miracle treatment to avoid organ rejection. After its discovery as an effective immunossupresor, several alternative treatments have been established, including another macrolide lactone derivate known as FK506, which was isolated from Streptomyces tsukubaensis, and firstly described in 1987. Soon after, scientists, upon discovering the intracellular molecular targets of these immunosuppressants, defined a new family of proteins known as immunophilins.

Today, the immunophilin family has been subdivided into three main categories attending its sensitivity to immunosuppressants: cyclophilins, FKBPs and an additional uncharacterized CsA- and FK506-binding proteins subfamily. The most relevant functional property of immunophilins is their chaperone activity or peptidyl prolyl isomerase activity (PPI), which results inhibited upon complexing either with CsA or FK506. In this sense, the immunophilin chaperone activity is crucial for the correct folding and subsequent activation of many intracellular regulatory proteins. Moreover, many cellular functions attributed to this family involve interaction, and formation of heterotrimeric complexes, with the serine/threonine phosphatase calcineurin (CNa or PP2B). The latter contributed to misleadingly believe that CsA and FK506 are specific CNa inhibitors. In the last decades of the last century, scientists discovered the relevance of the serine/threonine kinase mTOR in cell cycle proliferation, cancer, apoptosis, and immunossuppression. The study of the cellular molecular target of rapamycin, revealed that, as for CsA and FK506, rapamycin and some of its derivates complexed with an immunophilin isotype and, subsequently, acquired the ability to complex with mTOR and reduced its kinase activity.

The reviews in the present hot topic contribute to a better understanding of this important family of proteins. In fact, after the detailed historical review of transplants by Cubero and collaborators, authors describe several alternative strategies to the use of immunophilin antagonists, in order to avoid graft rejection once the medical procedures take place. Cubero and his team have supervised kidney transplant in the Infanta Cristina Hospital for more that 20 years and explain the latest protocol of immunosupression used nowadays.

The structure and multiple cellular functions of immunophilins are detailed by Christian Lucke and Matthias Weiwad. These authors describe in detail the structure of the two major immunophilin groups, cyclophilins and FKBPs. The residues targeted during CsA and FK506 interaction with the peptidyl-prolyl isomerase active domain of immunophilins are analyzed in detail. Lucke and Weiwad further review some of the most relevant cellular events where immunophilins have been involved.

Dr. Hausch provides the readers with an updated list of chemical tools used to prevent immunophilin activity. His group has been involved in the development of fluorescent derivates to explore the role of immunophilins in several cellular processes. The structure of the molecules is completed with a wide number of references in which these compound have been tested, thus providing a detailed information of the cellular behaviour of each compound. A new technical application to these compounds has also been suggested, which consist in the use of immunophilin binding agents to produce protein dimerization, thus receiving the name of chemical dimerizers.

The involvement of immunophilins in neurodegenerative disorders is summarized by Dr Yoon et al. Since a neurotrophic effect was attributed to FK506 and rapamycin, the role of immunophilins in neurons has received much attention, and resulted in the demonstration that immunophilins participate in neurone growth, protection against oxidant insults, and neurotransmitter release. This review also summarizes the latest information regarding the role of different immunophilins in severe neurological diseases such as Parkinson, Alzheimer, Huntington, and amyothrophic lateral sclerosis disease. This review is complemented by that of Park and coworkers, which directly defines neuroimmunophilin ligands (NILs) as all immunophilin antagonists with neurological regulatory properties, and summarizes the current experimental evidences supporting the beneficial effects of NILs administration.....

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986711798194414

Publication date: December 1, 2011

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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