Research and Development of Small Molecule Fusion Inhibitors Against Viruses

The Type I enveloped viruses (such as HIV, coronavirus, influenza virus, etc.) have caused significant public health events globally, including AIDS, influenza pandemics, and the recent COVID-19 pandemic, which are characterized by rapid transmission, high pathogenicity, and frequent mutations, posing a serious threat to human health. These viruses are mediated by fusion proteins at the early stage for infecting host cells, and the six-helix bundle (6-HB) formed by fusion protein conformational change is the crucial structure for viral membrane fusion and the target for fusion inhibitors. Small molecule fusion inhibitors, compared to peptide-based agents, offer advantages including superior oral bioavailability, metabolic stability, and lower production cost, thereby potentially reducing resistance risk. Their mechanism of targeting conserved fusion machinery highlights potential for developing broad-spectrum agents, as evidenced by activity against distinct viruses such as HIV and coronaviruses. Thus, the development of small-molecule fusion inhibitors has become an important breakthrough for antiviral agent research and development. This narrative review summarizes the research progress of small-molecule fusion inhibitors targeting viral fusion proteins (such as HIV envelope protein, coronavirus spike protein, influenza virus hemagglutinin), aiming to provide novel design pathways based on fusion inhibition strategies and fresh perspectives on antiviral R&D.