Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded RNA viruses and are divided into Alphaand Beta-coronaviruses. CoVs infect mammals and birds and typically result in lower and/or upper respiratory tract disease. The spectrum of illness in humans caused by CoVs range from common colds to worldwide epidemics/pandemics, including severe acute respiratory syndrome (SARS-CoV) in 2003, human CoV-NL63 in 2004, human CoV-HKU1 in 2005, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. There are no approved vaccines or antiviral drugs to combat CoV infections and a lack of tested and validated therapeutics represents a tremendous global concern with respect to the current SARSCoV-2 outbreak. At the end of December 2019, the World Health Organization became aware of an abnormally large cluster of pneumonia cases localized in the city of Wuhan, China. Within a span of only 3 months, over one million confirmed cases of COVID-19 have been diagnosed worldwide with almost 50,0000 resulting in death. The numbers in the US are now growing at an alarming rate (currently ~25% of the global total) as well as the number of deaths (currently ~10% of total). The severity of human CoV infections and high mortality rates were strikingly apparent in 2002 with the first SARS-CoV pandemic in Guangdong, China, as well as the MERS-CoV outbreak in 2012. Like SARS-CoV, the current SARS-CoV-2, which is 79% identical, also employs angiotensin converting enzyme II (ACE2) as the host receptor for cellular entry. The CoV surface-exposed spike (S) protein is responsible for the recognition and binding of ACE2 and represents a potential target for development of vaccines and antiviral therapeutics. Importantly, antibodies (Abs) isolated to date from COVID-19 patients appear to bind several regions on the spike protein that then represent ideal targets for small molecule discovery. The spike protein on the CoV surface is a glycosylated trimer and consists of two extracellular domains, S1 and S2. The majority of nAbs (neutralizing Abs) to CoVs characterized to date target the S1 domain that contains the receptor-binding domain (RBD) responsible for ACE2 binding. Notwithstanding, Abs with epitopes on the S2 domain, consisting of the stem fusion machinery, also have neutralizing potential in both cell-based and animal models of infection and are generally more broadly reactive against other CoVs than those antibodies that target S1. Additionally, a helical peptide EK1 derived from the HR2 domain of human CoV-OC43 (a strain responsible for the common cold) broadly binds to the stem region of CoVs and inhibits membrane fusion. Our goal with this supplement is to define the neutralizing epitopes on the S protein of SARS-CoV-2, such as those targeted by antibodies, the EK1 peptide and other peptides reported to bind to the RBD, to aid in both structure-based vaccine and small molecule antiviral design. Specifically, we will leverag...