7-Substituted pterins provide a new direction for ricin A chain inhibitors

• Published in: European journal of medicinal chemistry 2011-09, Vol.46 (9), p.3608-3615
• Main Authors: Pruet, Jeff M., Jasheway, Karl R., Manzano, Lawrence A., Bai, Yan, Anslyn, Eric V., Robertus, Jon D.
• Format: Article
• Language: English
• Subjects: 7-Substituted derivatives; Biological and medical sciences; Crystallography, X-Ray; Fluorometry; Kinetics; Luciferase assay; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Models, Molecular; Pharmacology. Drug treatments; Pterin; Pterins - chemistry; Pterins - pharmacology; Ricin - antagonists & inhibitors; Ricin inhibitors; Spectrometry, Mass, Electrospray Ionization; Temperature
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.05.025

Ricin is a potent toxin found in castor seeds. The A chain, RTA, enzymaticlly depurinates a specific adenosine in ribosomal RNA, inhibiting protein synthesis. Ricin is a known chemical weapons threat having no effective antidote. This makes the discovery of new inhibitors of great importance. We have previously used 6-substituted pterins, such as pteroic acid, as an inhibitor platform with moderate success. We now report the success of 7-carboxy pterin (7CP) as an RTA inhibitor; its binding has been monitored using both kinetic and temperature shift assays and by X-ray crystallography. We also discuss the synthesis of various derivatives of 7CP, and their binding affinity and inhibitory effects, as part of a program to make effective RTA inhibitors. [Display omitted] ► Several new pterin compounds were synthesized and analyzed. ► Many compounds showed good inhibition of ricin toxin A in an in vitro assay. ► Nearly all of these compounds were observed through X-ray crystallography to be bound within the active site of RTA. ► The success of these compounds indicates a greater affinity of 7-substituted pterins, compared to the regioisomeric 6-derivatives.