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Title
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WIN 52035-2 inhibits both attachment and eclipse of human rhinovirus 14.
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Authors
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D.A.Shepard,
B.A.Heinz,
R.R.Rueckert.
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Ref.
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J Virol, 1993,
67,
2245-2254.
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PubMed id
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Abstract
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WIN compounds inhibit attachment of human rhinovirus 14 by binding to a
hydrophobic pocket within the capsid and inducing conformational changes in the
canyon floor, the region that binds the cellular receptor. To study the basis of
drug resistance, we isolated and characterized a family of human rhinovirus 14
mutants resistant to WIN 52035-2. Thermostabilization data and single-cycle
growth curves provided evidence for two classes of resistant mutants. One class,
here called exclusion mutants, showed a marked decrease in drug-binding affinity
and was characterized by substitution to bulkier amino acid side chains at two
sites lining the hydrophobic pocket. The other class, called compensation
mutants, displayed single-amino-acid substitutions in the drug-deformable
regions of the canyon; these mutants were able to attach to cells despite the
presence of bound drug. A delay in the rise period of the growth curves of
compensation mutants indicated a second locus of drug action. WIN 52035-2 was
found to inhibit the first step of uncoating, release of VP4. Attempts to
identify this site of drug action by using single-step growth curves were
obscured by abortive elution of a major fraction of cell-attached virus. The
drug had no effect on the rate of this process but did affect the spectrum of
particles produced.
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