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Structural studies on human rhinovirus 14 drug-resistant compensation mutants
A T Hadfield1, M A Oliveira, K H Kim
1Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-1392, USA.
Journal of Molecular Biology
|October 13, 1995
Summary
Structural analysis of human rhinovirus 14 (HRV14) compensation mutants reveals how mutations affect antiviral drug resistance. Mutations enhancing cell binding and altering drug interactions explain viral resistance mechanisms.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- Human rhinovirus 14 (HRV14) is a common cause of the common cold.
- Antiviral capsid binding compounds, such as WIN 52035 and WIN 52084, target HRV14.
- Understanding resistance mechanisms is crucial for developing effective antiviral therapies.
Purpose of the Study:
- To determine the structures of HRV14 compensation mutants resistant to antiviral compounds.
- To elucidate the structural basis of resistance and altered viral-host interactions.
Main Methods:
- X-ray crystallography was used to determine the three-dimensional structures of HRV14 mutants.
- Site-directed mutagenesis was employed to create specific mutations.
- Comparative structural analysis was performed between wild-type and mutant viruses.
Main Results:
- Mutations in the viral canyon enhance binding to host cells (ICAM).
- Mutations within the VP1 hydrophobic pocket reduce the affinity for WIN compounds.
- The binding sites for cellular receptors and WIN compounds overlap, leading to competitive binding.
Conclusions:
- Compensation mutants shift the equilibrium towards receptor binding, conferring resistance.
- Mutations impact both viral entry and drug binding affinity.
- Structural insights provide a basis for designing next-generation antiviral agents.