Sialic Acid Biology
Sialic acids are a type of nine-carbon sugars that occur at the end of sugar chains attached to glycoproteins, glycolipids, and glycosaminoglycans. The most common sialic acid in humans is N-acetylneuraminic acid (Neu5Ac) and its derivatives, and it can be connected to sugar chains by several different linkages, with α2,3- and α2,6-linkages particularly relevant for human infectious disease. Certain viruses and bacteria can bind to sialic acids as a requirement for entry and infection of cells.
Influenza viruses typically have preference for binding to sialic acids with either α2,3- or α2,6-linkages, with the specific preference of one over the other dependent on the influenza subtype. Parainfluenza viruses show selectivity with parainfluenza virus type 1 (PIV1) recognizing sialic acids with α2,3-linkages, and parainfluenza virus type 3 (PIV3) recognizing sialic acids with α2,3- or α2,6-linkages.
A New Class of Antiviral
Ansun recognized the difficulty of targeting viral infections because of virus mutation and the ability to evade traditional antiviral treatments. In response we developed an innovative approach for fighting respiratory viruses by targeting the host receptor instead of the virus.
This has led to the creation of DAS181, a first-in-class recombinant sialidase protein designed to remove sialic acids located on the surface of epithelial cells lining the human respiratory tract. These sialic acids are naturally present on cell surfaces and are needed by some viruses for viral entry into cells. Cleavage of sialic acid inactivates the mechanism for viral entry and infection, interrupting the virus lifecycle and giving patients the chance to recover.
In research and preclinical studies, DAS181 has been shown to have antiviral activity against all types of human parainfluenza. DAS181 has also been shown to have potent antiviral activity against all subtypes of influenza A and B, including subtypes of concern such as H1N1, H5N1, and H7N9. DAS181 is also active against drug-resistant influenza, including influenzas resistant to Tamiflu (oseltamivir) and Relenza (zanamivir).
Parainfluenza viruses (PIV) bind to sialic acid receptors located on ciliated cells in the respiratory tract, and they replicate in those cells. PIV infection is the second most common cause of acute respiratory tract infections among children less than 5 years age, and has been estimated to cause approximately 18% of all cases of croup. Some children have serious illness requiring hospitalization. Among healthy adults, PIV infections are usually mild, self-limited upper respiratory tract infections with typical cold symptoms. However, in immunocompromised patients, the virus is much more likely to migrate to the lower respiratory tract, with viral pneumonia developing in up to 50% of patients. Some of these patients will develop severe disease requiring hospitalization. The reported mortality rates of these patients are high ranging from 25% to 55% within 30 days after the diagnosis of lower respiratory tract disease.
In these severely patients, DAS181 is delivered to the pulmonary surface by nebulization where the sialidase domain can cleave sialic acids for antiviral effect. A Phase 2 clinical trial for treatment of lower tract parainfluenza infection in immunocompromised patients yielded promising results and was the basis for the US Food and Drug Administration (FDA) granting DAS181 Breakthrough Therapy designation. DAS181 is currently being evaluated in a Phase 3 clinical trial in hospitalized immunocompromised patients infected with parainfluenza virus.