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standing viral physiology will be highlighted. This will be followed by a description of capsid-binding
antirhinoviral compounds. We will leave discussions of other HRV targets, e.g., proteases, to other
authors more knowledgeable in these subjects. Drug structure—activity relationships will be discussed,
followed by a discussion of drug resistance. Finally clinical trials and future prospects for capsidbinding
inhibitors in any antirhinoviral armamentarium will be discussed.
II. The Human Rhinovirus Anatomy
The human rhinoviruses are picornaviruses (pico = small; rna = RNA), a family of small (300 Å in
diameter), positive sense, single-stranded RNA viruses. Other generas in this family include the
enteroviruses (e.g., polioviruses); the aphthoviruses (e.g., foot-and-mouth disease virus); the
cardioviruses (e.g., mengovirus, EMC virus); and the heparnaviruses (e.g., hepatitis A virus). With the
exception of the heparnaviruses, a crystallographic structure is known for at least one of the viruses in
each genera [5,11–17]. These structures show remarkable similarities, which will be described. In spite
of these similarities, caution should be exercised when trying to generalize data gathered in one genus to
other members of the picornavirus family.
The picornaviruses share an icosahedral structure (Figure 1). The icosahedral protein coat that
encapsidates the viral RNA is made up of 60 symmetrically arranged protomers. Each of these
protomers is comprised of four viral polypeptides, termed VP1 through VP4. This was the extent of our
structural knowledge of the picornaviruses until the 1985 structure of HRV14 was published by Michael
Rossmann and coworkers [16]. This was followed rapidly by structural determination of a variety of
other picornaviruses. These structures provided the framework on which to base current paradigms for
the picornaviral life cycles, particularly with regard to their assembly, attachment, and uncoating.
The VP1, VP2, and VP3 all contain a core eight-stranded antiparallel β barrel (Figure 2). These
polypeptides have surfaces on both the exterior and interior of the virion particle, facing both solvent
and viral RNA. The fourth polypeptide, VP4, is considerably smaller than the others and does not
contain the eight-stranded barrel motif. The VP4 resides entirely on the interior surface of the virion, in
close association with the viral RNA. The N-terminus of VP4 is known to be myristoylated in both rhino-
and polioviruses [18,19].
Three regions of the picornavirus structure deserve special attention because they appear to play crucial
roles in the viral life cycle as well as bear on the function of the capsid-binding compounds. These
regions are the canyon, the VP1 hydrophobic pocket, and the β cylinder.
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