Prodrug approach for increasing cellular glutathione levels

Abstract

Reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and antioxidant defense. It plays an important role in many cellular processes, such as cell differentiation, proliferation and apoptosis. GSH deficiency has been observed in aging and in a wide range of pathologies, including neurodegenerative disorders and cystic fibrosis (CF), as well as in several viral infections. Use of GSH as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties. Several reports have provided evidence for the use of GSH prodrugs able to replenish intracellular GSH levels. This review discusses different strategies for increasing GSH levels by supplying reversible bioconjugates able to cross the cellular membrane more easily than GSH and to provide a source of thiols for GSH synthesis.

Scheme 1

Biosynthesis of GSH.

Figure 1

Biological functions of GSH.

Figure 2

GSH ester prodrugs.

Figure 3

Transport and cleavage of GDE prodrug as proposed by Levy et al. [79].

Figure 4

S-acyl-GSH prodrugs.

Figure 5

L-CySSG prodrug.

Figure 6

Disulfide bond reduction of L-CySSG prodrug as proposed by Berkeley et al. [88].

Figure 7

L-Thiazolidine-4-carboxylic acids.

Figure 8

L-2-Oxothiazolidine-4-carboxylate.

Figure 9

Chemical structure of bucillamine.

Figure 10

Multifunctional GSH codrugs.

Figure 11

Glutathionyl conjugates.

Figure 12

Structure of UPF1.