Sea cucumber sugar blocks a key cancer enzyme

2025-07-15 09:02:00, Kuriozitete CNA

Sea cucumbers clean up organic debris that lies on the ocean floor and are otherwise known as the cleaners of the sea. While many people enjoy sea cucumbers, few know that these simple organisms produce complex sugar molecules that could lead to promising anti-cancer drugs.

Vitor Pomin, a glycobiologist at the University of Mississippi, and his colleagues previously showed that a sugar isolated from the sea cucumber Holothuria floridana, called fucosylated chondroitin sulfate (HfFucCS), inhibits sulfatase-2 (Sulf-2), an enzyme involved in cancer cell invasion.

Now, in a new study published in Glycobiology, Pomin and his team have identified a unique structural motif in HfFucCS that is responsible for its potent inhibition. Their discovery could inform future efforts to synthesize small molecule inhibitors against Sulf-2.

Over the past two decades, medicinal chemists have been trying to develop a potent inhibitor against Sulf-2, which is elevated in various types of cancer.

However, synthesizing Sulf-2 inhibitors in the lab is both difficult and expensive. This prompted Pomin to search the natural world for molecules that mimic heparan sulfate, which binds to Sulf-2.

Heparan sulfate is a glycosaminoglycan (GAG), which is a long chain of sugars that adorns the extracellular side of many transmembrane proteins on the surface of cells. In the past, Pomin and his colleagues have worked with numerous GAG analogs from marine organisms, including various species of sea urchins and sea cucumbers.

To investigate how well HfFucCS and other GAG analogs inhibit Sulf-2 activity, the team used a sulfatase activity assay developed in the lab of Georgetown University's Radoslav Goldman, a co-author of the study. The researchers found that among the molecules tested, HfFucCS was the most potent.

Because HfFucCS is a large and complex molecule, it can be difficult to synthesize in the lab and administer therapeutically. So Pomin and his colleagues wanted to identify the specific structural motif in HfFucCS that inhibits Sulf-2. Previously, the researchers had used depolymerization followed by size-exclusion chromatography to generate fragments of HfFucCS.

After narrowing down the potential binding sites for Sulf-2 in the HfFucCS fragment, the researchers performed computational molecular docking experiments to simulate the interaction of the fragment with Sulf-2. They identified a branched fucose 3,4-disulfate motif that is unique to HfFucCS and gave it its potency.

Rosen warned that as a heparan sulfate mimic, HfFucCS could have off-target effects that could lead to toxicity. Heparan sulfate interacts with many molecules, including various growth factors and chemokines, so theoretically, HfFucCS could interact with them as well.

Pomin's team previously showed that HfFucCS is minimally toxic in vitro, although Pomin acknowledged that these results were preliminary.

Since environmental biologists are already concerned about the overharvesting of sea cucumbers for food, Pomin is currently collaborating with a medicinal chemist to find a way to synthesize the potent HfFucCS fraction in the lab. He also plans to evaluate the potency and toxicity of HfFucCS in animal models overexpressing Sulf-2./ CNA