The emergence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the 2019 coronavirus disease (COVID-19), has erupted into a global pandemic that has led to
tens of millions of
infections and hundreds of thousands of deaths worldwide. The development of
therapeutics to treat
infection or as prophylactics to halt viral transmission and spread is urgently needed. SARS-CoV-2 relies on structural rearrangements within a spike (S)
glycoprotein to mediate fusion of the viral and host cell membranes. Here, we describe the development of a
lipopeptide that is derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibits
infection by SARS-CoV-2. The
lipopeptide inhibits cell-cell fusion mediated by SARS-CoV-2 S and blocks
infection by live SARS-CoV-2 in Vero E6 cell monolayers more effectively than previously described
lipopeptides. The SARS-CoV-2
lipopeptide exhibits broad-spectrum activity by inhibiting cell-cell fusion mediated by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) and blocking
infection by live MERS-CoV in cell monolayers. We also show that the SARS-CoV-2 HRC-derived
lipopeptide potently blocks the spread of SARS-CoV-2 in human airway epithelial (HAE) cultures, an ex vivo model designed to mimic respiratory viral propagation in humans. While viral spread of
SARS-CoV-2 infection was widespread in untreated airways, those treated with SARS-CoV-2 HRC
lipopeptide showed no detectable evidence of viral spread. These data provide a framework for the development of
peptide therapeutics for the treatment of or prophylaxis against SARS-CoV-2 as well as other coronaviruses.IMPORTANCE SARS-CoV-2, the causative agent of
COVID-19, continues to spread globally, placing strain on health care systems and resulting in rapidly increasing numbers of cases and mortalities. Despite the growing need for medical intervention, no FDA-approved
vaccines are yet available, and treatment has been limited to supportive
therapy for the alleviation of symptoms. Entry inhibitors could fill the important role of preventing initial
infection and preventing spread. Here, we describe the design, synthesis, and evaluation of a
lipopeptide that is derived from the HRC domain of the SARS-CoV-2 S
glycoprotein that potently inhibits fusion mediated by SARS-CoV-2 S
glycoprotein and blocks
infection by live SARS-CoV-2 in both cell monolayers (in vitro) and human airway tissues (ex vivo). Our results highlight the SARS-CoV-2 HRC-derived
lipopeptide as a promising therapeutic candidate for
SARS-CoV-2 infections.