Drug building blocks pave path to new sepsis treatments

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The immune system can typically ramp up the body's defenses to clear out an invading threat without issue. Glitches can happen, however, with sepsis occurring when the mustered army of cells also attacks the body's own tissues and organs as if they were enemy combatants.

Sepsis is dangerous, particularly when it isn't treated early, and it can lead to the even more deadly condition of septic shock—a massive drop in blood pressure that can quickly damage organs by starving them of nutrients. Treatments for sepsis are limited to antibiotics and supportive care as researchers have found it difficult to develop other effective therapies for the condition.

Scientists at Sanford Burnham Prebys and CUNY Advanced Science Research Center have published findings in ACS Omega demonstrating the promise of a new approach to uncovering potential treatments for sepsis.

The research team focused on an enzyme called Vaccinia-H1-related phosphatase (VHR) due to its role in controlling how the immune system responds when sensing danger. Previous studies have shown that genetically modifying mice to produce less VHR provided a safeguard against sepsis and septic shock.

Previous efforts to develop drugs that block VHR have not succeeded due to the nature of the "active site," the location where the enzyme binds to specific molecules to carry out its role in the immune system. In the new study, scientists took a different approach to uncovering ways to inhibit VHR.

"We built a fragment-based drug discovery platform for VHR," said Lutz Tautz, Ph.D., research associate professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys and senior and corresponding author of the study.

"This strategy looks for small molecular fragments that can interact with the enzyme and then uses the best ones as building blocks to create effective drug candidates."

The research team tested 1,000 fragments and identified multiple promising starting points for future drugs. The investigators showed that these favorable fragments were selective for VHR. This means that they did not also interact with similar enzymes, which should reduce side effects in drugs designed using the fragments.

In addition, Tautz and team discovered fragments capable of binding to VHR in previously unknown locations beyond the active site.

"Fragments that bind to novel sites could potentially be optimized to enable selective degradation of VHR for combating sepsis and septic shock—devastating conditions responsible for nearly 20% of global deaths," said Tautz.

"I think we've also demonstrated that this drug discovery platform can be applied to the superfamily of protein tyrosine phosphatases that VHR belongs to, which is meaningful as these important signaling molecules have been implicated in many diseases."

More information: Jiaqian Wu et al, Fragment Screening Identifies Novel Allosteric Binders and Binding Sites in the VHR (DUSP3) Phosphatase, ACS Omega (2025). DOI: 10.1021/acsomega.4c10321

Journal information: ACS Omega

Provided by Sanford-Burnham Prebys