New agent regulates serotonin production

Serotonin makes you feel good. This neurotransmitter known as the “happiness hormone” regulates mood, sleep, and appetite. It also plays a key role in the gastrointestinal tract, where it is involved in regulating intestinal movement and the release of fluids that are important for the digestion and absorption of nutrients.

But too much serotonin causes health problems. An oversupply of the hormone can disrupt normal bodily functions and trigger various diseases. Professor Michael Bader and Dr. Edgar Specker have developed a drug that specifically lowers serotonin levels. Bader leads the Molecular Biology of Peptide Hormones Lab at the Max Delbrück Center, while Specker heads the Compound Management Core Facility at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP). “We have now founded Trypto Therapeutics to bring our new therapeutic agent to the market,” says Bader. Along with the two scientists, biotech entrepreneurs Dirk Pleimes and Dr. Radoslaw Wesolowski are also involved in the new company. Max Delbrück Center and the FMP have an equity stake in the spin-off.

Stopped by the blood-brain barrier

Scientists don’t know exactly why serotonin production gets out of whack. An exception is carcinoid syndrome, a tumor disease in which hormone-producing cells release inordinate amounts of serotonin. Carcinoid syndrome is often associated with diseases like pulmonary hypertension, intestinal diseases, and heart valve fibrosis. However, they can also occur in patients without carcinoid syndrome. As different as these diseases are, elevated serotonin is involved in the development of all of them.

This is where the molecule that Bader and Specker discovered and further developed in the FMP’s compound library comes into play. The starting structure was initially identified in the Screening Unit headed by Jens von Kries. The successful identification of this promising screening hit marked the beginning of the furhter development process in the research group of Medicinal Chemistry, led by Marc Nazaré. There, extensive chemical modifications and optimizations were carried out in order to improve the efficacy, stability and safety of the molecule.
The optimized molecule is called TPT-004 and inhibits an enzyme found in gastrointestinal tract cells, called tryptophan hydroxylase (TPH), that plays a role in serotonin synthesis. Lower TPH activity means less serotonin circulating through the body. The researchers showed that the administration of TPT-004 improves the health of rats with pulmonary hypertension. They were also able to prove that this molecule cannot cross the blood-brain barrier in mice. This is important because serotonin is also produced in the neurons – a process that should not be blocked because the brain requires the neurotransmitter to function properly.

Venture capital needed to move forward

A great deal of funding has gone into developing the TPH inhibitor so far – through the Max Delbrück Center’s Pre-GoBio funding scheme, through various lines of funding from the German Federal Ministry of Education and Research (BMBF), the ZIM program of the German Federal Ministry for Economics and Climate Action (BMWK) (16KN073251) and, most recently, through the Max Delbrück Center’s SPOT spin-off support program. “We’ve received around €4.5 million in total,” says Bader. “But public third-party funding is not enough to take the next step. We need venture capital to do this. That’s why we founded Trypto Therapeutics.”

The scientists first plan to develop a method for producing their therapeutic agent in pure form in sufficient quantities so that it can be used in human clinical trials. They will also carry out a toxicity study in order to investigate the risks and possible side effects of the compound. Only then will it be possible to conduct a phase I clinical trial on a small group of healthy volunteers. “If we successfully complete the phase I trial, we will then decide whether to conduct a subsequent phase II study or sell the whole thing,” says Bader. The researchers initially want to test the drug on patients with pulmonary hypertension. If this works, they want to examine whether TPT-004 helps treat other diseases associated with elevated serotonin levels. Their development pipeline also includes new inhibitors for other enzymes.

Text: Jana Ehrhardt-Joswig

Pressekontakte MDC
 

Professor Michael Bader
Head of the lab “Molecular Biology of Peptide Hormones”
Max Delbrück Center
+49 (0)30 9406 2193
mbader@mdc-berlin.de

Christina Anders
Editor, Communications Department
Max Delbrück Center
+49 (0)30 9406 2118
christina.anders@mdc-berlin.de or presse@mdc-berlin.de