Synthesis and Biological Evaluation of a γ-Cyclodextrin-based Formulation of the Anticancer Agent 5,6,11,12,17,18,23,24-Octahydrocyclododeca[1,2-b:4,5-b’:7,8-b’’:10,11-b’’’]tetraindole (CTet)

none10sìopenLucarini, Simone; DE SANTI, Mauro; Antonietti, Francesca; Brandi, Giorgio; Diamantini, Giuseppe; Fraternale, Alessandra; Paoletti, MARIA FILOMENA; Tontini, Andrea; Magnani, Mauro; Duranti, AndreaLucarini, Simone; DE SANTI, Mauro; Antonietti, Francesca; Brandi, Giorgio; Diamantini, Giuseppe; Fraternale, Alessandra; Paoletti, MARIA FILOMENA; Tontini, Andrea; Magnani, Mauro; Duranti, Andre

GSH and analogs in antiviral therapy

Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment. GSH is the most powerful intracellular antioxidant and plays a role in the detoxification of a variety of electrophilic compounds and peroxides via catalysis by glutathione-S-transferases (GST) and glutathione peroxidases (GPx). As a consequence, the ratio of reduced and oxidized glutathione (GSH:GSSG) serves as a representative marker of the antioxidative capacity of the cell. A deficiency in GSH puts the cell at risk for oxidative damage. An imbalance in GSH is observed in a wide range of pathologies, such as cancer, neurodegenerative diseases, cystic fibrosis (CF), several viral infections including HIV-1, as well as in aging. Several reports have provided evidence for the use of GSH and molecules able to replenish intracellular GSH levels in antiviral therapy. This non-conventional role of GSH and its analogs as antiviral drugs is discussed in this chapter. (C) 2008 Elsevier Ltd. All rights reserved

Antiviral and Immunomodulatory Properties of New Pro-Glutathione (GSH) Molecules.

Reduced glutathione (GSH) is present in millimolar concentrations in mammalian cells. It is involved in many cellular functions such as detoxification, amino acid transport, production of coenzymes, and the recycling of vitamins E and C. GSH acts as a redox buffer to preserve the reduced intracellular environment. Decreased glutathione levels have been found in numerous diseases such as cancer, viral infections, and immune dysfunctions. Many antioxidant molecules, such as GSH and N-acetylcysteine (NAC), have been demonstrated to inhibit in vitro and in vivo viral replication through different mechanisms of action. Accumulating evidence suggests that intracellular GSH levels in antigen-presenting cells such as macrophages, influence the Th1/Th2 cytokine response pattern, and more precisely, GSH depletion inhibits Th1-associated cytokine production and/or favours Th2 associated responses. It is known that GSH is not transported to most cells and tissues in a free form. Therefore, a number of different approaches have been developed in the last years to circumvent this problem. This review discusses the capacity of some new molecules with potent pro-GSH effects either to exert significant antiviral activity or to augment GSH intracellular content in macrophages to generate and maintain the appropriate Th1/Th2 balance. The observations reported herein show that pro-GSH molecules represent new therapeutic agents to treat antiviral infections and Th2-mediated diseases such as allergic disorders and AID

Expression of IL-12 p40 and IL-27 p28 mRNA in murine peritoneal macrophages.

<p>The peritoneal macrophages were obtained as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057866#s4" target="_blank">Materials and Methods</a> section. They were left untreated or treated with either 20 mM GSH-C4 or 20 mM I-152 for 2 hours and further stimulated with LPS and IFN-γ for 3 and 6 hours as indicated in the figure. Total RNA extraction and reverse transcription as well as IL-12 p40 and IL-27 p28 mRNA quantification were performed as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057866#s4" target="_blank">Materials and Methods</a> section. The results are the mean±S.D. of 4 values. *p<0.05 vs. Control.</p

STAT-mediated activation of gene transcription by IFN-γ.

<p>The binding of ligand (IFN- γ) to the receptor results in receptor oligomerization and subsequent activation of receptor-associated JAK tyrosine kinases (JAK1 and JAK2). Activated JAKs phosphorylate specific tyrosine residues in the cytoplasmic domain of the receptor which in turn serves as the docking sites for the cytoplasmic transcription factors known as STAT-1. STAT-1 are therefore recruited to the phosphorylated receptor and subsequently phosphorylated by JAKs. The phosphorylated STAT-1 then dimerize, leave the receptor, and translocate to the nucleus where they activate the transcription of several genes, such as IRF-1. I-152, increasing intracellular thiol content, may positively influence JAK2’s catalytic activity which is known to be directly regulated by the redox state of the cell. I-152 may inhibit protein tyrosine phosphatases by glutathionylation. Y: tyrosine; GAS: IFN-γ activation site.</p