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against most of the HRV serotypes to be useful in approximately 50% of common colds. This
percentage may be somewhat higher because some of the other causes of cold-like illnesses, particularly
the enteroviruses (e.g., Coxsackie and echoviruses), are also inhibited by capsid-binding compounds
[5–7]. In order to be efficacious, drugs must necessarily have a broad spectrum of activity.
The second difficulty in producing HRV chemotherapy stems from the relatively innocuous nature of
HRV infection. Compounds must be able to be very safely administered, with a minimum of drug-drug
interactions, if therapy is to be acceptable. An analogy may be drawn between common headache
remedies and common cold chemotherapy. Common headache cures such as nonsteroidal
antiinflammatory agents and acetaminophen clearly can cause serious side effects (gastrointestinal
bleeding or catastrophic liver failure) particularly if misused [8]. In spite of this possibility, serious
complications from these agents are quite rare. One would suspect that an antirhinoviral agent would
need to be at least as safe as headache remedies.
The third major difficulty in developing cold cures arises from the fact that the HRVs are RNA viruses.
When presented with any selective pressure, including chemotherapeutic or antibody challenge, RNA
viruses mutate rapidly [9]. This ability to mutate is most clearly illustrated in influenza viruses (RNA
viruses), where new strains continuously arise to circumvent immunity in a population. Influenza A
viruses have been shown to mutate around the anti-influenza drug Amantadine, after a single passage
through a susceptible human host. The mutated viruses shed from a host treated with Amantadine are
now resistant to Amantadine. These mutated viruses appear to be as virulent as the parent strain of virus
[10].
Any effort at antirhinoviral therapy must attend to these three issues: (1) serotypic diversity; (2)
exceptional safety; and (3) viral resistance. Therefore, any structure-based approach cannot concentrate
on potency alone, but must also attend to these three issues as well. The requirement for inhibiting
multiple targets has been addressed in tangible ways using structure-based design and will be discussed
here. Safety issues have been addressed in limited published data from clinical and preclinical studies,
but structure-based design has not played any significant role in addressing these problems. One might
argue that structure-based approaches have aided in the design of clinical backups. These backups are
then brought forward after an initial drug fails for safety reasons. Drug-resistant mutations created in the
laboratory have also been examined structurally and will be discussed. The importance of resistance
developing in the clinical setting has not yet been answered.
This chapter will first introduce the target, the HRVs, and describe their anatomy and life cycle.
Emphasis will be placed on the viral capsid and its disassembly or uncoating. How structural
information has helped in our under-
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