Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors

Abstract

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

Keywords: SARS-CoV-2; cancer chemotherapy; diabetes; dicarbonyl stress; glyoxalase; malaria; methylglyoxal; resveratrol.

Figure 1

The glyoxalase system and protein and DNA glycation by methylglyoxal. (A) Metabolism of MG by the glyoxalase system. (B) Formation of hydroimidazolone MG-H1 from arginine residues. (C) Formation of imidazopurinone MGdG in DNA. Adduct residue is shown with guanyl base only.

Figure 2

Proposed mechanism of action of Glo1 inducer, tRES-HESP, through suppression of the unfolded protein response. Key: yellow filled arrows—mechanism of health improvement by; red filled arrows—damaging processes suppressed. See text for details. Abbreviations: GRP78, 78 kDa glucose-regulated protein; IRE1α; inositol regulated enzyme-1α; Maf, basic region leucine zipper-type transcription factor; miR-17. microRNA-17; Nrf2, nuclear factor-erythroid factor 2-related factor 2; TXNIP, thioredoxin-interacting protein; XBP1, X-box binding protein-1. Modified and reproduced with permission from [50].

Figure 3

Delivery of glyoxalase 1 inhibitor, S-p-bromobenzylglutathione, into cells by diester modification. Abbreviations: BBG, S-p-bromobenzylglutathione; BBGD, S-p-bromobenzylglutathione cyclopentyl diester; and γ-GT, γ-glutamyl transferase.