Review GSH and analogs in antiviral therapy Alessandra Fraternale a, * , Maria Filomena Paoletti a , Anna Casabianca a , Lucia Nencioni b , Enrico Garaci c , Anna Teresa Palamara b , Mauro Magnani a a Department of Biomolecular Sciences, University of Urbino ‘‘Carlo Bo”, Via Saffi 2, 61029 Urbino (PU), Italy b Pharmaceutical Microbiology Section, Department of Public Health ‘‘G. Sanarelli”, University of Rome ‘‘La Sapienza”, Rome, Italy c Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘‘Tor Vergata”, Rome, Italy article info Article history: Received 23 May 2008 Received in revised form 15 September 2008 Accepted 15 September 2008 Keywords: Reduced glutathione (GSH) Pro-GSH molecules Antiviral drugs Viral infections Oxidative stress Th1/Th2 response abstract 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 vari- ety of electrophilic compounds and peroxides via catalysis by glutathione-S-transferases (GST) and glutathione peroxidases (GPx). As a consequence, the ratio of reduced and oxi- dized glutathione (GSH:GSSG) serves as a representative marker of the antioxidative capac- ity 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 dis- eases, cystic fibrosis (CF), several viral infections including HIV-1, as well as in aging. Sev- eral 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 ana- logs as antiviral drugs is discussed in this chapter. Ó 2008 Elsevier Ltd. All rights reserved. Contents 1. Introduction ............................................................................................ 100 2. GSH and RNA virus infections .............................................................................. 101 2.1. HIV and other viruses causing immunodeficiency in animals ............................................... 101 2.2. Influenza and parainfluenza viruses.................................................................... 105 2.3. Rhinovirus ........................................................................................ 106 2.4. Hepatitis viruses ................................................................................... 106 3. GSH and DNA virus infections .............................................................................. 107 3.1. Herpes simplex viruses .............................................................................. 107 4. Conclusions ............................................................................................. 108 Acknowledgements ...................................................................................... 108 References ............................................................................................. 108 0098-2997/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mam.2008.09.001 * Corresponding author. Tel.: +39 722 305241; fax: +39 722 305324. E-mail address: alessandra.fraternale@uniurb.it (A. Fraternale). Molecular Aspects of Medicine 30 (2009) 99–110 Contents lists available at ScienceDirect Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam