HA2-focused library

ChemDiv’s library of chemically diverse small molecule targeting hemagglutinin-2 related to flu viruses contains 3,569 compounds

The influenza virus is a significant cause of respiratory infections and is responsible for 20,000–40,000 deaths annually in the United States alone, with numbers increasing up to 10 folds during pandemic years. Viral subtypes are categorized based on the sequences of hemagglutinin (HA) and neuraminidase (NA) surface proteins, with only H1N1, H3N2 subtypes, and B-type viruses currently circulating within the human population. Recent years have seen the emergence of highly pathogenic avian influenza strains, such as H5N1, identified as the culprits behind severe flu cases in humans and flagged for their pandemic potential.

Influenza viruses infect respiratory tract cells by binding to the plasma membrane and entering via the endocytic pathway. Hemagglutinin (HA) plays a pivotal role in this process as the most abundant surface antigen, facilitating both binding and fusion. This membrane glycoprotein comprises two disulfide-linked polypeptide chains, HA1 and HA2, with the latter featuring a hydrophobic sequence known as the fusion peptide. HA is the primary target for neutralizing antibodies during infection, necessitating annual vaccine updates to combat its rapid mutation rate. Although HA2 exhibits greater conservation than HA1 (about 90% vs. 67% for Influenza A H1 and H3 subtypes in surface-exposed regions), suggesting potential as a "universal" vaccine candidate, initial antigenic mapping revealed that neutralizing antibodies primarily target the receptor-binding HA1 subunit. The interaction sites for HA2 are predominantly within the regions of residues 7–46 and 290–321 of HA1.

Our small molecule library targeting hemaglutinin-2 (HA2) presents a strategic advantage in the field of drug discovery, especially for influenza therapeutics. HA2 is a subunit of the hemagglutinin protein found on the surface of the influenza virus,] that plays a crucial role in the viral entry process into host cells. It mediates membrane fusion, an essential step for viral replication. Given its more conserved nature across various influenza strains compared to HA1, targeting HA2 offers the potential for developing broad-spectrum antiviral agents. Such a library would enable the identification of compounds that can interfere with the fusion process, effectively blocking the virus's ability to infect host cells. This approach not only has the potential to yield treatments that are effective against a wide range of influenza subtypes, including seasonal and pandemic strains but also reduces the likelihood of resistance development due to the conserved nature of the HA2 subunit.

Furthermore, our small molecule library focused on HA2 could significantly accelerate the drug discovery process by providing a diverse array of lead compounds for optimization and development. By going after an important part of the virus's life cycle, these molecules might work in a different way than current flu medicines, which mostly go after neuraminidase or the HA1 subunit. The development of HA2 inhibitors could complement current vaccination strategies by providing an additional line of defense against influenza, especially in cases where vaccines are less effective due to antigenic drift or shift. Additionally, the exploration of such a library could uncover new insights into the structure-function relationships of HA2, further informing the design of potent and selective inhibitors. Ultimately, the availability of a small molecule library targeting HA2 represents a promising avenue for the discovery of new antiviral drugs with the potential for broad applicability and long-term effectiveness in combating influenza outbreaks.