Scientists have developed potentially groundbreaking drug-like molecules that could prevent influenza infection by targeting the first stage of the virus entering the body’s respiratory cells. These inhibitors focus on hemagglutinin, a protein on the surface of type A influenza viruses. The findings were published in the Proceedings of the National Academy of Sciences in May 2024, showing promise for developing a drug that can prevent influenza infection and possibly inhibit the virus’s spread after infection. The researchers believe these molecules have the potential to help prevent and treat seasonal flu infections without the need for yearly updates like vaccines.
The research began with the identification of a small molecule, F0045(S), with some capacity to bind and inhibit H1N1 type A influenza viruses. Through a high-throughput hemagglutinin binding assay, the researchers quickly screened large libraries of small molecules and found lead compound F0045(S). They then utilized “SuFEx click-chemistry” to tweak F0045(S)’s original structure and generate a large library of candidate molecules. Subsequent screening identified two molecules, 4(R) and 6(R), with superior binding affinity compared to F0045(S, laying the groundwork for further optimization.
Using X-ray crystal structures, the researchers were able to identify the binding sites of molecules 4(R) and 6(R), analyze their superior binding abilities, and pinpoint areas for improvement. When tested in cell culture, molecule 6(R) demonstrated non-toxicity and over 200-times improved cellular antiviral potency compared to F0045(S). The researchers then developed compound 7 through targeted optimization methods, proving to be the most potent small-molecule hemagglutinin inhibitor developed to date.
Future studies will focus on further optimizing compound 7 and testing its efficacy in animal models of influenza to assess its potential as an antiviral drug. While the inhibitors in this study specifically target H1N1 strains of influenza, researchers are working on developing equivalents to target other strains, such as H3N2 and H5N1. The team plans to address various properties of the inhibitors, including pharmacokinetics, metabolism, and aqueous solubility, to optimize their effectiveness.
Funding for this groundbreaking research was provided by the NIH, the Nathan Shock Institute of Aging Research, and Einstein-Montefiore. The collaboration between scientists at Scripps Research and the Albert Einstein College of Medicine has led to the development of drug-like molecules that could revolutionize the prevention and treatment of influenza infections. By targeting hemagglutinin and inhibiting the virus at the initial stage of infection, these inhibitors have the potential to provide a new approach to combating seasonal flu without the need for annual updates like traditional vaccines.