Since its emergence, SARS-CoV-2 has been the subject of intense investigation. Early sequence analysis identified a unique 13 amino acid region (13-mer) nested within the receptor-binding domain (RBD) of the spike protein that directly interacts with the ACE2 receptor. Blasting with the 13-mer identified a highly conserved segment in propyl-tRNA synthetase enzymes. Comparison with the human analogue, glutamyl-propyl-tRNA synthetase 1, showed a high level of identity with its drug binding domain, which is targeted by halofuginone, a drug recently shown to block SARS-CoV-2 infection in vitro. In silico experiments predicted a high affinity interaction between halofuginone and the 13-mer. In vitro addition of halofuginone effectively inhibited binding of recombinant S1 monomer to ACE2. Accordingly, it appears that halofuginone inhibits viral infection by preventing correct interactions between spike protein and ACE2. These findings indicate that viral entry can potentially be drug-targeted and support the application of halofuginone in mitigation of COVID-19.