Aminopeptidase N inhibitors and SARS

Sir

Since initiation of active epidemiological surveillance, the toll of severe acute respiratory syndrome (SARS) has continued to mount. As of April 14, 2003, the cumulative number of cases of SARS was 3169, and 144 deaths have been reported. This epidemic shows no signs of abatement, in part because the mechanism of transmission remains unclear and the agent(s) that causes disease elusive. However, a previously unknown coronavirus, with or without another viral copathogen, has been implicated in the pathogenesis of SARS.¹ The involvement of a member of the coronavirus family, a large group of sizeable single-stranded RNA viruses with multiple serotypes, natural hosts, and tissue specificities, is intriguing; these viruses have had a good host adaptation and are frequent causes of the common cold.² Life-threatening lower respiratory infections caused by coronaviruses are uncommon.²

There are gaps in our understanding of the immunopathogenesis of the respiratory injury caused by these viruses, although it could depend on release of inflammatory mediators.² No studies have been done on the mechanism of lung injury in coronaviridiae-induced pneumonia, but one would expect similar pathogenic events. Moreover, the antigenic diversity of coronaviridiae capable of causing respiratory infection remains uncertain.² There are several strains with a tropism to the human respiratory tract.² Although most of the known strains are related antigenically to the two principal and antigenically-distinct human coronavirus strains, 229E and OC43,² the SARS-causing coronavirus is a novel strain.¹

The lack of known antiviral treatment against coronaviridiae in the face of an epidemic creates a sense of urgency. The availability of agents that could modulate key events of the coronavirus replicative cycle, such as viral attachment to target cells, could have important therapeutic implications. Some insights with respect to host receptors of human coronaviridiae could help us to find ways of halting viral spread. Specifically, the human cell membrane-bound metalloproteinase, aminopeptidase N (CD13), is the receptor for coronavirus 229E (but not for OC43);³ aminopeptidase N is also a receptor for enteropathogenic coronaviruses,⁴ indicating some degree of ligand-receptor promiscuity. This cell-surface glycoprotein is expressed in many human tissues, including lungs.⁵ Moreover, aminopeptidase N is highly expressed in immune cells and in the activated vascular endothelium of sites of inflammation,⁵ potentially providing an entry site. Potent and selective inhibitors of this receptor—eg, ubenimex—do exist.⁵ Ubenimex has been used as an oral agent with limited toxicity in patients with cancer.⁵ Also, this drug has immunomodulatory effects⁵ that might attenuate virus-induced lung injury.

Since coronaviruses are the pathogen, or important copathogens, in SARS, blockage of aminopeptidase N with ubenimex or monoclonal antibodies should be explored as a prophylaxis in high-risk groups, such as health-care workers or other individuals in close contact with infected patients. Additionally, consideration should be given for pre-emptive ubenimex therapy to travellers returning from southeast Asia who develop pneumonia.