Viruses require entry proteins to penetrate the cells where they will replicate. The Severe Acute Respiratory Syndrome (SARS-CoV-2) version is called the S protein. The S protein is also the objective of the current vaccines, is rapidly adapting to its new human hosts. Its first major step in this direction early in 2020, when its amino acid 614 (of 1297) changed from an aspartic acid (D) to glycine (G). Viruses bearing this D614G mutation transmit in humans more rapidly and now form the majority in circulation.
Initially in the pandemic, in the scramble to create tools to study SARS-CoV-2, investigators developed pseudovirus systems to measure infection in a safe, easy, significant way. These systems express a viral entry protein on the surface of a reporter virus used to monitor cell entry and have been used for years to study many such proteins, including the S protein of “classic” SARS-CoV-1. Frustratingly, pseudoviruses developed from the SARS-CoV-2 S protein produced many nether signals than those based on the very similar SARS-CoV-1 S protein. This was puzzling because biochemical studies of SARS-CoV-1 and SARS-CoV-2 S-protein receptor binding domains (RBDs) made clear that the SARS-CoV-2 RBD bound their common receptor, angiotensin-converting enzyme 2 (ACE2), with higher affinity than that of SARS-CoV-1.
This is not a conclusion that most students of human coronaviruses would have predicted, given that SARS-CoV-1, which passes on with sensible effectiveness, lacks this site, whereas the more distantly related MERS coronavirus bears this site and transmits poorly. How the SARS-CoV-2 furin site promotes new human infections remains a key open question in the field.