Potential for receptor-based antiviral drugs against SARS

Abstract

Effective antiviral drugs to treat sudden acute respiratory syndrome (SARS) are needed. Several targets for development of drugs against this new coronavirus are being analysed, including prevention of virus entry, proteolytic processing of the polymerase polyprotein, RNA synthesis, virion assembly, and release. In their Correspondence letter, Dimitrios Kontoyiannis and colleagues (May 3, p 1558)1Kontoyiannis DP Pasqualini R Arap W Aminopeptidase N inhibitors and SARS.Lancet. 2003; 361: 1558Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar suggest that the receptor for the SARS coronavirus is CD 13 or human aminopeptidase N, apparently based on our work2Yeager CL Ashmun RA Williams RK et al.Human aminopeptidase N is a receptor for human coronavirus 229E.Nature. 1992; 357: 420-422Crossref PubMed Scopus (651) Google Scholar showing that aminopeptidase N is the receptor for human respiratory coronavirus 229E, which causes upper respiratory tract infection. We showed that some monoclonal antibodies directed against aminopeptidase N blocked virus binding and entry into susceptible cells. We also showed that a blocking monoclonal antibody directed against murine CEACAM1a, the receptor for murine coronavirus (mouse hepatitis virus; MHV), inhibits murine coronavirus infection in vitro and in vivo.3Williams RK Jiang GS Holmes KV Receptor for mouse hepatitis virus is a member of the carcinoembryonic antigen family of glycoproteins.Proc Natl Acad Sci USA. 1991; 88: 5533-5536Crossref PubMed Scopus (309) Google Scholar, 4Smith AL Cardellichio CB Winograd DF de Souza MS Barthold SW Holmes KV Monoclonal antibody to the receptor for murine coronavirus MHV-A59 inhibits viral replication in vivo.J Infect Dis. 1991; 163: 879-882Crossref PubMed Scopus (33) Google Scholar Thus, monoclonal antibodies or Fab fragments directed against a receptor for SARS coronavirus could be useful in prevention or treatment of SARS in close contacts of infected individuals. However, there is no experimental evidence to suggest that aminopeptidase N is a receptor for SARS coronavirus. Importantly, the aminoacid sequences of the spike glycoproteins of SARS coronavirus, human respiratory coronavirus 229E, and murine coronavirus differ greatly, especially in the N-terminal, receptor-binding domain, S1. Kontoyiannis and co-workers also suggested that the putative SARS coronavirus receptor activity of aminopeptidase N could be blocked with a small molecule that inhibits its enzymatic activity, ubenimex, and suggested that this molecule be explored to prevent infection of health-care workers with SARS coronavirus and to treat travellers returning from southeast Asia who develop pneumonia. Results of our studies2Yeager CL Ashmun RA Williams RK et al.Human aminopeptidase N is a receptor for human coronavirus 229E.Nature. 1992; 357: 420-422Crossref PubMed Scopus (651) Google Scholar indicate that high concentrations of ubenimex or actinonin, both small competitive inhibitors of the enzymatic activity of aminopeptidase N, are unable to inhibit infection with human coronavirus strain 229E. Moreover, the enzymatic activity of aminopeptidase N is not needed for its use as a receptor for group 1 coronaviruses.5Delmas B Gelfi J Kut E Sjostrom H Noren O Laude HJ Determinants essential for the transmissible gastroenteritis virus-receptor interaction reside within a domain of aminopeptidase-N that is distinct from the enzymatic site.Virology. 1994; 68: 5216-5224Google Scholar Since aminopeptidase N has not been established as a cellular receptor for SARS coronavirus, and since competitive inhibitors of aminopeptidase N do not inhibit human coronavirus 229E recognition of its aminopeptidase N receptor, it is not reasonable to use ubenimex to prevent or treat SARS. Identification of a receptor for SARS coronavirus would be an important first step toward discovery of receptor-based antivirals for prophylaxis or therapeutics. Such antivirals, however, should be firmly established through in-vitro and preclinical testing before being considered for use against SARS.