Small-molecule acts as broad-band influenza entry blocker

The small molecule, code-named JNJ4796, targets a part of viral hemagglutinin (HA), which is common to all influenza A group 1 viruses but not found on group 2 and influenza B viruses. Binding of JNJ4796 to this HA stem structure blocked influenza virus form infecting mouse and human bronchial epithelial cells in a petri-dish. Furthermore, in mice given the drug orally, it prevented animals from getting sick after being exposed to lethal doses (25 times the median lethal dose) of multiple strains of the flu.

JNJ4796 stands for a new class of antibody-mimicking small molecules that prevent the downsides of antibody therapy such as immunogenicity, high manufacturing cost, and administration as infusion or injection. Maria von Dongen and colleagues screened the drug candidate from a molecule library of 500,000 small molecules based on its capacity to replace HB80.4 bound to the HA stem, an antibody previously discovered by a team from University of Washington to bind to 5 motives in the HA stem of influenza A group 1 viruses.

The authors claim their results provide a proof-of-concept for antibody-guided, small molecule discovery and pave the way for a new class of orally administered “antibody mimetic” drugs, which may neutralize a variety of viral infections.

Each year, influenza epidemics cause millions of cases of severe illness and nearly 500,000 deaths worldwide. However, currently available seasonal vaccines offer limited protection against the various subtypes of the virus. The discovery of human broadly neutralizing antibodies (bnAbs) such as HB80.4 or its parent antibody CR6261 that neutralize the virus by targeting its hemagglutinin (HA) stem have opened the door for the development of broad spectrum (“universal”) influenza vaccines.