biostudies-literatureUnknown17(3)Yin N<b>Background:</b> Glutathione (GSH) is an essential antioxidant that protects against oxidative stress, but its oral bioavailability is below 1% due to enzymatic degradation and poor gastrointestinal absorption. Improving the oral bioavailability of GSH could significantly enhance its therapeutic efficacy. <b>Methods:</b> This study synthesised GSH analogues with chemical modifications to improve bioavailability. Seven GSH derivatives were designed: three analogues with altered stereochemistry (<b>1.62</b>, <b>1.63</b>, and <b>1.64</b>) and three <i>N</i>-methylated derivatives (<b>1.65</b>, <b>1.70</b>, and <b>1.71</b>), alongside a native GSH (<b>1.61</b>). The analogues were synthesised via Fmoc-solid-phase peptide synthesis, and they were characterised using reverse-phase high-performPharmaceutics385https://www.ebi.ac.uk/biostudies/studies/S-EPMC11945201biostudies-literatureEnhancing the Oral Bioavailability of Glutathione Using Innovative Analogue Approaches.PMC11945201Wen JLiu MChen GYin NBrimble MAHarris PWRSun JfalseEnhancing the Oral Bioavailability of Glutathione Using Innovative Analogue Approaches.<b>Background:</b> Glutathione (GSH) is an essential antioxidant that protects against oxidative stress, but its oral bioavailability is below 1% due to enzymatic degradation and poor gastrointestinal absorption. Improving the oral bioavailability of GSH could significantly enhance its therapeutic efficacy. <b>Methods:</b> This study synthesised GSH analogues with chemical modifications to improve bioavailability. Seven GSH derivatives were designed: three analogues with altered stereochemistry (<b>1.62</b>, <b>1.63</b>, and <b>1.64</b>) and three <i>N</i>-methylated derivatives (<b>1.65</b>, <b>1.70</b>, and <b>1.71</b>), alongside a native GSH (<b>1.61</b>). The analogues were synthesised via Fmoc-solid-phase peptide synthesis, and they were characterised using reverse-phase high-perform2025-01-01T00:00:00Z2025 Mar2025-07-04T03:06:04.246Z2025-07-04T03:06:04.246ZS-EPMC119452014014304910.3390/pharmaceutics17030385