Aldehyde dehydrogenase 2 (ALDH2) and glucose-6-phosphate dehydrogenase (G6PD) deficiencies are the two most prevalent enzymopathies worldwide, effecting ~8% and ~6% of the world’s population, respectively. However, despite their prevalence, there are no treatments for these disorders. We used high throughput screening (HTS) to identify compounds which correct these enzymopathies. From these screens, we identified Alda-1, a small molecule that increases mutant ALDH2, ALDH2*2, activity by two-fold and found that Alda-1 works by stabilizing distant a-helical interactions (Figure 1). Additionally, we identified AG1, a molecular chaperone of G6PD that interacts with and stabilizes an allosteric NADP<sup>+</sup> at the dimer interface, promoting the active form of G6PD – the dimer (Figure 1). Unlike ALDH2, which has one prevalent mutation, G6PD deficiency has multiple single-point mutations common in the population. Interestingly, AG1 activated several common Class II/III G6PD mutants, suggesting modulation of oligomerization may be a therapeutic strategy for correcting multiple unique genetic mutations. However, AG1 was unable to correct the most severe form of G6PD deficiency, Class I. Using proof of concept mutagenic strategies, we now find that stabilizing the tetramer improves protein stability and activity for Class I variants, with stability and activity being major determinants of pathogenicity. Future work includes medicinal chemistry to improve AG1 and the identification of a small molecule which stabilizes the tetramer, with the goal to correct all classes of G6PD deficiency.

Correcting enzymopathies with small molecules: The discovery of small molecule chaperones for ALDH2 and G6PD deficiency

ACS Fall 2021

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