Abstract
Several 7-peptide-substituted pterins were synthesized and tested as competitive active-site inhibitors of ricin toxin A (RTA). Focus began on dipeptide conjugates, and these results further guided the construction of several tripeptide conjugates. The binding of these compounds to RTA was studied via a luminescence-based kinetic assay, as well as through X-ray crystallography. Despite the relatively polar, solvent exposed active site, several hydrophobic interactions, most commonly π-interactions not predicted by modeling programs, were identified in all of the best-performing inhibitors. Nearly all of these compounds provide IC₅₀ values in the low micromolar range.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding, Competitive
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Catalytic Domain
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Chemical Warfare Agents* / chemistry
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Crystallography, X-Ray
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Hydrophobic and Hydrophilic Interactions
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Kinetics
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Luminescent Measurements
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Models, Molecular*
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Molecular Structure
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Protein Binding
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Pterins / chemical synthesis*
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Pterins / chemistry
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Pterins / pharmacology
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Ricin / antagonists & inhibitors*
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Ricin / chemistry
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Structure-Activity Relationship
Substances
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Chemical Warfare Agents
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Oligopeptides
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Pterins
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Ricin