Abstract
We have previously reported the discovery and initial SAR optimization of the first series of inhibitors of the human papillomavirus type-11 (HPV11) E1-E2 protein-protein interaction. These inhibitors featured an indandione system spiro-fused onto an all syn substituted tetrahydrofuran ring. In this paper, we report new SAR efforts which have led to the identification of the first low nanomolar inhibitor of the HPV11 E1-E2 protein-protein interaction. In addition, we report a combined NMR and computational chemistry approach which allowed the successful determination of the absolute stereochemistry of the active species originating from the initial racemic lead.
MeSH terms
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacology*
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Chemistry, Pharmaceutical
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Chromatography, High Pressure Liquid
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Computational Biology
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Computer Simulation
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DNA-Binding Proteins / antagonists & inhibitors*
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Epoxy Compounds / chemistry
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Human papillomavirus 11 / drug effects*
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Human papillomavirus 11 / metabolism
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Humans
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Indicators and Reagents
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Conformation
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Spectrometry, Mass, Electrospray Ionization
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Stereoisomerism
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Structure-Activity Relationship
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Viral Proteins / antagonists & inhibitors*
Substances
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Antiviral Agents
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DNA-Binding Proteins
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E1 protein, Human papillomavirus type 11
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E2 protein, Human papillomavirus type 11
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Epoxy Compounds
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Indicators and Reagents
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Viral Proteins