Tetrahydrobiopterin (BH4) in chronic disease

Tetrahydrobiopterin (BH4) is a tightly regulated cellular metabolite that affects a variety of neuronal and inflammatory cell functions. BH4 is produced by three enzymatic pathways: 1) de novo synthesis pathway; 2) salvage pathway; and 3) recycling pathway¹. At steady state, cellular BH4 homeostasis is primarily regulated through the salvage and recycling pathways.

De novo BH4 production is significantly increased in injured or hyperactive peripheral nociceptors, as well as in a variety of immune cells, including T cells^2,3, macrophages^4,5 and dendritic cells⁶. As a small molecule cofactor for amino acid hydroxylases, nitric oxide synthases and alkylglycerol monooxygenase, increased levels of BH4 have a pluripotent effect on a variety of downstream pain and inflammatory mediators^7,8,9.

Multiple human genetic studies have linked a haplotype in the gene encoding GTP cyclohydrolase I, a BH4 synthetic enzyme, to a reduced risk of developing chronic pain after nerve injury or chronic disease⁷. Carriers of this haplotype have an inability to up-regulate BH4 synthesis in response to injury leading to better clinical outcomes in chronic pain settings^7,10-14. Importantly, these carriers have normal baseline levels of BH4, no deficits in normal pain sensation, and none of the clinical symptoms associated with the congenital deletion mutations in the BH4 synthesis pathway genes^7,13,14.

Recent studies have also demonstrated that sulfasalazine and other structurally-related sulfa drugs are potent inhibitors of sepiapterin reductase (SPR), the final enzyme in the de novo synthesis pathway^16-18. Sulfasalazine has been used clinically for over 60 years to treat autoimmune indications, such as ulcerative colitis and rheumatoid arthritis, despite a lack of understanding of the drug’s molecular mechanism of action. Linking the clinical activity of this approved drug to its modulation of BH4 synthesis provides an additional tie to human disease biology.

Safely restoring BH4 levels back to baseline by targeting one of the key BH4 synthetic enzymes has been shown to reduce inflammation and pain hypersensitivity in preclinical models^7,15,19. Quartet is advancing its drug discovery efforts to develop small molecule therapies that can safely mimic the human genetic observations with pharmacological intervention.

References

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