Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and β-mercaptoethylamine

Abstract

Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-β-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and β-mercaptoethylamine or cysteamine, MEA). NAC is a precursor of L-cysteine, while MEA is an aminothiol able to increase GSH content; thus, I-152 represents the very first attempt to combine two pro-GSH molecules. In this review, the in-vitro and in-vivo metabolism, pro-GSH activity and antiviral and immunomodulatory properties of I-152 are discussed. Under physiological GSH conditions, low I-152 doses increase cellular GSH content; by contrast, high doses cause GSH depletion but yield a high content of NAC, MEA and I-152, which can be used to resynthesize GSH. Preliminary in-vivo studies suggest that the molecule reaches mouse organs, including the brain, where its metabolites, NAC and MEA, are detected. In cell cultures, I-152 replenishes experimentally depleted GSH levels. Moreover, administration of I-152 to C57BL/6 mice infected with the retroviral complex LP-BM5 is effective in contrasting virus-induced GSH depletion, exerting at the same time antiviral and immunomodulatory functions. I-152 acts as a pro-GSH agent; however, GSH derivatives and NAC cannot completely replicate its effects. The co-delivery of different thiol species may lead to unpredictable outcomes, which warrant further investigation.

Intracellular Redox-Modulated Pathways as Targets for Effective Approaches in the Treatment of Viral Infection

“…I-152, a codrug of NAC and S-acetyl-mercaptoethylamine (SMEA) linked together by an amide bond, is deacetylated to the corresponding dithiol derivative, which may release NAC and MEA ( Figure 3 B) [ 120 ]. It was synthesized with the aim to design a new potent lipophilic antioxidant molecule with improved delivery properties of the two compounds.…”

“…There are not certain data about the mechanism of action whereby I-152 can inhibit HIV replication. However, in the light of capacity of I-152 to provide high amounts of different molecules carrying SH groups, such as NAC, MEA, cysteine and GSH [ 120 ], I-152 may interfere with both early and late steps in the HIV biological cycle.…”

Can Vitamin D and L-Cysteine Co-Supplementation Reduce 25(OH)-Vitamin D Deficiency and the Mortality Associated with COVID-19 in African Americans?

“…A link has been established between impaired immunity associations and reduced cellular levels of GSH (33). GSH or its precursor L-cysteine has been used to replenish intracellular GSH levels in anti-viral therapy (34). An imbalance in both GSH homeostasis and oxidative stress is an essential component of the inflammation and respiratory distress common not only to aging, but also to a variety of diseases, such as diabetes, chronic obstructive pulmonary disease, acute respiratory distress syndrome, tuberculosis, neurodegenerative diseases, and several viral infections, including HIV (in humans) and SIV (in rhesus macaques) (33,35,36).…”

Activation of NRF2 and ATF4 Signaling by the Pro-Glutathione Molecule I-152, a Co-Drug of N-Acetyl-Cysteine and Cysteamine

“…The molecule is deacetylated on the MEA moiety and hydrolyzed within the cells to release NAC and MEA, two well-known pro-glutathione compounds. I-152 has been shown to efficiently boost GSH both in vivo and in vitro, under physiological and pathological conditions characterized by GSH depletion (i.e., viral infection) (reviewed in [ 22 ]). Little is known about the mechanism of action of I-152.…”