 The ongoing global pandemic of coronavirus disease 2019, COVID-19, caused by severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, has had devastating effects on public health and the global economy. Viral antigenic evolution has resulted in the continuous generation of new variants, including the recently expanding Armacron subvariant, which is capable of immunovasion from most of the existing neutralizing antibodies, NABS. This has presented new challenges for the prevention and treatment of COVID-19. Exploring broad-spectrum antiviral agents to combat the emerging variants is therefore essential. In stark contrast to the massive accumulation of mutations within the SARS-CoV-2RBD, the S2 fusion subunit has remained highly conserved among variants. As such, S2-based therapeutics may offer effective cross-protection against new SARS-CoV-2 variants. We have summarized the most recently developed broad-spectrum fusion inhibitors, NABS, peptids, proteins, and small molecules, and candidate. This article was authored by Li Anguo, Xiong Lin, Zemin Chen, and others.