A specific and fundamentally new major depression (MD) treatment for the 40% of patients without an effective therapeutic, which inhibits sulfotransferase to regulate serotonin in the brain and can be used in combination with existing drugs (MAOIs/SSRIs).
One in five individuals worldwide will suffer from major depression (MD), a prevalent, recurrent mental health condition. In the past year, more than 20 million Americans (including adolescents) have experienced an MD episode. Individuals struggling with depression experience a number of debilitating symptoms, which include persistent sadness, irritability, sleep irregularities, appetite changes, and feelings of hopelessness. Furthermore, suicide, the 10th leading cause of death in the United States, is 20-fold more likely to occur during an MD episode.
Symptoms manifest as the result of decreased neurotransmitter levels in the brain, specifically serotonin, which is heavily implicated in mood and mood regulation. Current MD therapeutics include both selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs), both of which increase serotonin availability in the brain.
Unfortunately, there is lack of long-term treatment as many patients initially respond to these therapeutics but later experience a recurrence of symptoms. This issue, specifically with respect to MAOIs, is thought to be due to the increased activity of sulfotransferases, which also act on serotonin, as compensation for the loss of MAO activity. Due to a lack of potent and selective inhibitors, sulfotransferases have not been established as drug targets – until now.
Our solution is to target SULTs as a novel approach to the treatment of MD. SULTs are enzymes that transfer a sulfuryl group (SO3) to substrate molecules. They have an important role in cellular metabolism, as they either detoxify or activate a number of drugs, hormones, neurotransmitters, toxins, and carcinogens.
Our preliminary data suggests that targeting SULT1A3-mediated serotonin metabolism will increase the therapeutic effectiveness of current MD treatments. The isoform SULT1A3 is expressed in the brain and is primarily responsible for regulating serotonin levels. We anticipate that by inhibiting both oxidation (MAO) and sulfonation (SULT) of neurotransmitters, we will achieve an enhanced therapeutic response in MD patients.
Through the discovery of a novel allosteric binding site within the enzyme, our team has discovered the first potent and selective inhibitors of SULT1A3. Our top compound, CMP13, demonstrates not only outstanding affinity for SULT1A3 but also completely inhibits its activity in a cellular environment. Moreover, we have successfully used the same allosteric inhibitor to inhibit a related sulfotransferase (SULT1A1) and enhanced the efficacy of acetaminophen (Tylenol) in humans.
Overall, we have set the stage for translating this work into animals as an essential next step toward clinical testing. Furthermore, we are currently extending this strategy of identifying novel allosteric binding sites and selective inhibitors to additional disease-relevant SULT enzymes.
The competitive landscape analysis below summarizes key features of this solution, and current competitors working to solve similar healthcare problems.
Our initial preclinical work in mice is necessary in order to design inhibitor efficacy experiments in more complex models, such as non-human primates (NHPs). The experiments in NHPs are essential as they express the SULT1A3 isoform, like humans. Unfortunately, NHP studies were not feasible within the budget constraints of the PInCh award, however we will leverage the comprehensive mouse data to pursue additional funding opportunities from both federal and private entities to perform preclinical evaluation NHPs and ultimately, humans. For clinical trials we intend to partner with pharmaceutical companies or potentially establish a new biotech startup in Pittsburgh, an ideal location due to the rich scientific environment in neurological disorders at UPMC, Pitt, and CMU.
Additionally, we will apply the knowledge gained from our work with SULT1A3 to the identification of selective and potent inhibitors for other SULT isoforms. SULTs are involved in a number of diseases, including neurodegenerative disorders, anxiety, depression, skin diseases, obesity, and several cancers. Ideally, this award (and our work) will impact more patients than those suffering from depression. Until now, SULTs have essentially been an “undruggable” enzyme class. However, this award will ultimately allow us to demonstrate SULT inhibitors as potential “first in class” drugs.
Is another depression therapeutic necessary?
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D), which is the largest MD clinical trial, concluded that treatments that act as alternative modes of serotonin regulation are needed in this field moving forward. SULT inhibitors are a novel approach to serotonin regulation!
Why is co-treatment of SULT inhibitors and MAOIs necessary?
Serotonin inactivation by SULTs continues in patients currently taking MAOIs to treat their depression, which is why a recurrence of symptoms is common. Co-treating patients with both SULT and MAO inhibitors will prevent serotonin inactivation entirely and dramatically increase its availability in the brain.
What other SULTs have been drug targets?
Currently, SULTs have not been established as drug targets since their high degree of structural homology has hindered the development of selective inhibitors. This is because prior inhibition approaches have focused on targeting the conserved active site of SULTs. Our approach identifies and exploits allosteric sites on SULT enzymes for selective inhibitor development thereby, for the first time, validating the druggability of SULT enzymes.
Can this inhibition approach be extended to other SULT isoforms, i.e., can other SULTs be targeted by allosteric inhibitors?
Yes! Our team is currently working on the extension of this approach – identifying allosteric sites for inhibitor development – to alternative disease-relevant SULT isoforms. Stay tuned!