SAR of L-ABBA analogs for GGT1 inhibitory activity and L-ABBA's effect on plasma cysteine and GSH species

Ganesh Bist; Nguyen T Luong; Kazi Md Mahabubur Rahman; Donna M Ruszaj; Chenglong Li; Marie H Hanigan; Youngjae You

doi:10.1016/j.bmcl.2023.129406

SAR of L-ABBA analogs for GGT1 inhibitory activity and L-ABBA's effect on plasma cysteine and GSH species

Bioorg Med Chem Lett. 2023 Aug 15:92:129406. doi: 10.1016/j.bmcl.2023.129406. Epub 2023 Jul 7.

Authors

Ganesh Bist¹, Nguyen T Luong¹, Kazi Md Mahabubur Rahman¹, Donna M Ruszaj¹, Chenglong Li², Marie H Hanigan³, Youngjae You⁴

Affiliations

¹ Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, United States.
² Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, United States.
³ Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
⁴ Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, United States. Electronic address: yjyou@buffalo.edu.

PMID: 37423504
DOI: 10.1016/j.bmcl.2023.129406

Abstract

Gamma-glutamyl transferase 1 (GGT1) is a critical enzyme involved in the hydrolysis and/or transfer of gamma-glutamyl groups of glutathione, which helps maintain cysteine levels in plasma. In this study, we synthesized L-ABBA analogs to investigate their inhibitory effect on GGT1 hydrolysis and transpeptidase activity, with the goal of defining the pharmacophore of L-ABBA. Our structure-activity relationship (SAR) study revealed that an α-COO^- and α-NH₃⁺ group, as well as a two-CH₂ unit distance between α-C and boronic acid, are essential for the activity. The addition of an R (alkyl) group at the α-C reduced the activity of GGT1 inhibition, with L-ABBA being the most potent inhibitor among the analogs. Next, we investigated the impact of L-ABBA on plasma levels of cysteine and GSH species, with the expectation of observing reduced cysteine levels and enhanced GSH levels due to its GGT1 inhibition. We administered L-ABBA intraperitoneally and determined the plasma levels of cysteine, cystine, GSH, and GSSG using LCMS. Our results showed time- and dose-dependent L-ABBA changes in total plasma cysteine and GSH levels. This study is the first to demonstrate the regulation of plasma thiol species upon GGT1 inhibition, with plasma cystine levels reduced by up to ∼ 75 % with L-ABBA (0.3 mg/dose). Cancer cells are highly dependent on the uptake of cysteine from plasma for maintaining high levels of intracellular glutathione. Thus, our findings suggest that GGT1 inhibitors, such as L-ABBA, have the potential to be used in GSH reduction thereby inducing oxidative stress in cancer cells and reducing their resistance to many chemotherapeutic agents.

Keywords: Cysteine; Cystine; GGT1; GSH; GSSG; L-ABBA; SAR.