Rhinoviruses are the most common infectious agents of humans. They are the principal etiologic agents of afebrile viral upper-respiratory-tract infections (the common cold). Human rhinoviruses (HRVs) comprise a genus within the family Picornaviridae. There are >100 serotypically distinct members of this genus. In order to better understand their phylogenetic relationship, the nucleotide sequence for the major surface protein of the virus capsid, VP1, was determined for all known HRV serotypes and one untyped isolate (HRV-Hanks). Phylogenetic analysis of deduced amino acid sequence data support previous studies subdividing the genus into two species containing all but one HRV serotype (HRV-87). Seventy-five HRV serotypes and HRV-Hanks belong to species HRV-A, and twenty-five HRV serotypes belong to species HRV-B. Located within VP1 is a hydrophobic pocket into which small-molecule antiviral compounds such as pleconaril bind and inhibit functions associated with the virus capsid. Analyses of the amino acids that constitute this pocket indicate that the sequence correlates strongly with virus susceptibility to pleconaril inhibition. Further, amino acid changes observed in reduced susceptibility variant viruses recovered from patients enrolled in clinical trials with pleconaril were distinct from those that confer natural phenotypic resistance to the drug. These observations suggest that it is possible to differentiate rhinoviruses naturally resistant to capsid function inhibitors from those that emerge from susceptible virus populations as a result of antiviral drug selection pressure based on sequence analysis of the drug-binding pocket.Human rhinoviruses are the most common viral infectious agents in humans (9). In the United States, rhinoviruses account for more than one billion cases annually of viral respiratory tract infections (VRTI; i.e., the common cold) (34). The National Center for Health Statistics estimated that in 1996, 62 million cases of the common cold required medical attention or resulted in restricted activity in the United States (33). During this period, colds caused 45 million days of restricted activities and 22 million days lost from school. Roughly one in six colds results in a doctor's office visit, and up to 50% of these visits result in an antibiotic prescription (15,29,35,47). In 1998, more antibiotic prescriptions were written for presumed VRTIs than for bacterial infections, at a cost of approximately $726 million (14). Such inappropriate antibiotic prescribing is a major contributing factor to the development of drug-resistant bacterial pathogens (4,28,35,48). The total economic impact of non-influenza-related VRTI in terms of both direct (health care resource use) and indirect (productivity loss) costs approaches $40 billion annually (11).HRVs comprise a genus within the family Picornaviridae. Picornaviruses are small, nonenveloped viruses containing a single strand of message sense RNA. The RNA is protected by a protein coat or capsid composed of 60 copies of each of four structur...

Pleconaril is a broad-spectrum antirhinovirus and antienterovirus compound that binds into a hydrophobic pocket within viral protein 1, stabilizing the capsid and resulting in the inhibition of cell attachment and RNA uncoating. When crystals of human rhinovirus 16 (HRV16) and HRV14 are incubated with pleconaril, drug occupancy in the binding pocket is lower than when pleconaril is introduced during assembly prior to crystallization. This effect is far more marked in HRV16 than in HRV14 and is more marked with pleconaril than with other compounds. These observations are consistent with virus yield inhibition studies and radiolabeled drug binding studies showing that the antiviral effect of pleconaril against HRV16 is greater on the infectivity of progeny virions than the parent input viruses. These data suggest that drug integration into the binding pocket during assembly, or at some other late stage in virus replication, may contribute to the antiviral activity of capsid binding compounds.

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