Researchers present a newly identified small molecule influenza inhibitor, which, when administered orally, is capable of protecting mice from extremely lethal doses of influenza. It achieves this effect by mimicking broadly neutralizing antibodies, the authors say. The study's results provide a proof-of-concept for antibody-guided, small molecule discovery and pave the way for a new class of "antibody mimetic" drugs, which could one day be used to 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) that neutralize the virus by targeting its hemagglutinin (HA) stem have opened the door for the development of broad spectrum ("universal") influenza vaccines. Unlike antibodies, however, small molecule drugs are well-suited for oral delivery and could be a desirable alternative to bnAbs, the authors say. Based on the structural knowledge of the interactions and molecular mechanism of anti-stem bnAb CR6261, Maria van Dongen and colleagues engineered a small molecule compound capable of neutralizing a wide range of influenza viruses. Van Dongen et al. screened nearly 500,000 small molecule compounds using the AlphaLISA (Amplified Luminescent Proximity Homogeneous Assay) technology to discover those that selectively targeted the CR6261 epitope on the HA stem of the virus. The authors singled out a compound that demonstrated a promising ability to bind with a broad spectrum of influenza types and further optimized its chemistry to create JNJ4796 - a bioavailable small molecule 'antibody mimetic' that replicates bnAb functionality. According to the results of in vivo evaluation, oral administration of the compound protected mice from extremely lethal doses of H1N1 influenza - more than 25 times the median lethal dose - and greatly increased their survivability during continued exposure. Furthermore, the molecule neutralized viral infection in human bronchial epithelial cells.
###
Journal
Science