Relevance to Antiviral Drug Developments

At present, there are no clinically useful anti-coronavirus drugs, however, the targets for such drugs are clearly in sight. One obvious target is the coronavirus-encoded 3CL protease, as it is essential for the post-translational processing of gene 1 polyproteins into functional subunits ((Ziebuhr et al., 1995; see Figure 4.5). Structure-based, rational anti-3CL protease drug design is at a relatively advanced stage (Anand et al., 2003) and protease inhibitors roughly analogous to those used to combat HIV infection may be forthcoming. A second target, one that is far more relevant to the topic of this chapter, is the S protein. S proteins cause a characteristic syncytial cytopathology in the lung epithelia of SARS patients (Kuiken et al., 2003), and should the S protein dissections described above link syncytial activities with pathogenicity in animal models, investigations would reasonably focus on drugs designed to block S function.

Therapeutics designed to block S-receptor interactions constitute one strategy. Recent structure determinations for a group 2 coronavirus receptor (Tan et al., 2002), and delineation of relevant peptide loops interacting with S proteins (Rao et al., 1997), bring promise to the hypothesis that S-binding receptor fragments might be constructed and used to interfere with virus entry. Such a peptide drug might block infection by inducing the premature triggering of the fusion reaction (Figure 4.4). One must, however, be cautious about advocating this approach because, while many soluble receptors will drive S proteins unproductively into denatured states, some will clearly trigger productive fusion reactions (Matsuyama and Taguchi, 2002). As was found in studies with HIV and soluble CD4 (Moore et al., 1992; Arthos et al., 2002), virus infectivities may be enhanced rather than neutralized.

A second strategy might extend from current hypotheses concerning coronavirus neutralization by antibodies. Several potently neutralizing monoclonal antibodies bind S in regions between CEACAM-binding and fusion-inducing domains (Dalziel et al., 1986). While the mechanisms of neutralization are far from clear, one hypothesis is that the antibodies interfere with conformational transitions linking receptor interaction with fusion activation. High-resolution images of these antibody-S interactions could serve as a guide to construct smaller peptide ligands that neutralize infection by restricting global S conforma-tional change.

Finally, recent convincing evidence that the S proteins of the group 2 mouse hepatitis coronavirus carry out a "class-1" fusion reaction (Bosch et al., 2003) make it probable that several coronaviruses including SARS-CoV will be sensitive to a HR peptide-based fusion inhibition. Peptides derived from the HR regions of structurally similar retroviruses and paramyxoviruses interfere with fusion by associating with complete spikes during the activation reaction, preventing the appropriate collapse into a coiled-coil bundle (Wild et al., 1994; Yao and Compans, 1996; see Figure 4.4). Similarly, a small 38-residue peptide representing mouse hepatitis virus HR2 powerfully inhibited both virus-cell and cell-cell fusion, reducing these activities by several logs when present at 10 ^M concentration (Bosch et al., 2003). These HR2 peptides block entry by binding transient intermediate conformations of the fusion protein, depicted in Figure 4.4B, C. It will therefore be important to know whether the genetic variabilities inherent in the coronavirus S proteins alter receptor affinities or fusion kinetics, as these parameters determine the lifespan of the drug-sensitive intermediate structures (Reeves et al., 2002), and by extension they determine whether HR2-based peptides will be effective antiviral agents. By combining comparative studies on S protein receptor binding and membrane fusion with investigations of HR peptide-based antiviral activities, a mechanistic understanding of antiviral action will develop that can lay the groundwork required to develop therapies for human and animal diseases caused by the coronaviruses.

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