Fish tales: marine molecule with antiviral bite

Shark attack

Synchrotron small-angle X-ray scattering has been used to study details of squalamine, a molecule found in the dog fish, that has now been shown to have broad-spectrum antiviral properties in addition to previously known medicinal effects.

Squalamine, an aminosterol, was identified in the liver and other tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus) to much media fanfare in the mid-1990s as this compound and the chemically unrelated triterpene hydrocarbon squalene, were thought to be the source of the shark's ability to avoid cancer. However, despite the much discussed misconception that sharks do not get cancer, it emerged that squalamine does indeed have anticancer and antibiotic properties and so researchers continued with their investigations even as the media attention died down. It has proved to be a broad-spectrum antibiotic as well as an inhibitor of blood vessel growth, angiogenesis, a feature essential to tumour formation and also to a rare disease in which damage connective tissues takes on the chemical characteristics of bone, it ossifies on fibrodysplasia ossificans progressive. It has also proven useful in the eye disease, age-related macular degeneration.

Now, antiviral activity has been demonstrated by a team comprising the discoverer of squalamine Michael Zasloff of Georgetown University Medical Center, in Washington, DC, and colleagues there and at the University of Texas Medical Branch, Galveston, Northwestern University, Evanston, IL, Eastern Virginia Medical School, Norfolk, VA, Fox Chase Cancer Center, Philadelphia, PA, National Polytechnic Institute of Mexico, Utah State University, Logan, University of California, Los Angeles.

The fact that squalamine has been through several human clinical trials for the treatment of cancer and eye disorders means it has a well-characterised safety record. "This should allow more rapid regulatory approval for clinical testing as an antiviral agent," Zasloff told us. Indeed, efficacy against several viral pathogens, for which no approved therapy exists, has now been demonstrated. It might open up antiviral agents against dengue and yellow fever, and hepatitis, although the researchers are yet to home in on a specific target for testing, Zasloff reveals.

Squalamine potential

"To realize that squalamine potentially has broad antiviral properties is immensely exciting, especially since we already know so much from ongoing studies about its behaviour in people," explains Zasloff. Although it is a misconception that sharks do not get cancer or suffer from viral diseases, the findings do point to an explanation as to why, with their so-called "primitive" immune systems, they seem not to be as susceptible to viral infection and cancer as do mammals with the purportedly sophisticated immune systems.

"I believe squalamine is one of a family of related compounds that protects sharks and some other 'primitive' ocean vertebrates, such as the sea lamprey, from viruses," Zasloff adds. "Squalamine appears to protect against viruses that attack the liver and blood tissues, and other similar compounds that we know exist in the shark likely protect against respiratory viral infections." He adds that medical science might be able to harness the shark's immune system to convert all the animal's various antiviral compounds into protective agents against human disease. "That would be revolutionary," Zasloff says, "While many antibacterial agents exist, doctors have few antiviral drugs to help their patients, and few of those are broadly active."

Zasloff first identified squalamine in 1993 when he was a professor at the University of Pennsylvania. At the time, he was hoping to identify new antibacterial agents that would allow medicine to circumvent the growing problem of emerging bacterial resistance to conventional antibiotics. He was intrigued by the well-known ability of sharks to ward off disease despite their "primitive" immune systems. At the time, no one could explain why the shark was so hardy and the media attention around the discovery of squalamine inadvertently gave rise to the myth that sharks do not get cancer. They do.

As of 1995 it has been possible to synthesis the cholesterol-like structure of squalamine in the laboratory without resorting to extractions from shark liver and clinical trials have been run demonstrating its efficacy in various diseases. Zasloff was interested in the compound's net positive electrical charge and discovered that it because of this it can only enter certain cell types, such as liver cells and those from which blood capillaries are made. The negative charge disturbs positively charged proteins bound to negatively charged inner membrane of the cell wall as demonstrated by the team's synchrotron small-angle X-ray scattering experiments. These displaced proteins would normally by recruited by invading viral pathogens for replication. Without those proteins, Zasloff has found, the viral life cycle is disrupted.

Antiviral timing

"To me, the key to squalamine is that once in the body squalamine times its action to match the life cycle of most viruses," Zasloff says. "Most viruses take hours to complete their life cycle, the same time period that squalamine renders tissues and organs viral resistant after administration. In addition, it acts fast to stop viral replication, clearing the body of these predators within hours."

"The next steps involve testing the hypothesis in a human clinical trial," Zasloff revealed to SpectroscopyNOW. "I am in the process of selecting the specific viral hepatitis to be studied, and designing the appropriate early stage clinical trial."

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.