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

Abstract

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.

Baicalin Inhibits the Lethality of Ricin in Mice by Inducing Protein Oligomerization

“…For example, both purine-and pterin-like molecules form complexes with RTA wherein the compound docks into its active site (3,31). In our study, we also screened several inhibitors that bound to the active site of ricin with in vitro activity; however, this type of inhibitor showed no in vivo activity in the mouse model.…”

Optimized 5-Membered Heterocycle-Linked Pterins for the Inhibition of Ricin Toxin A

“…7 This was seen as a significant improvement over previous pterin-based inhibitors, which had activity at or above 600 μM. 8 Within this series, we reported a furan-linked pterin amide having an IC 50 of 380 μM.…”

Toxicity of ricin A chain is reduced in mammalian cells by inhibiting its interaction with the ribosome

“…The large size and polarity of the RTA active site make it a difficult target for drug development and the effectiveness of inhibitors that bind in or near this site has also been limited by issues of solubility and cell toxicity (Bai et al , 2010). Structure-based approaches have been used to identify inhibitors that block substrate binding to the active site (Bai et al , 2009; Pruet et al , 2011) or prevent an active-site residue from adopting an active confirmation (Pang et al , 2011). Other inhibitors have been identified using computer modeling approaches coupled with cell-based high throughput screens (Bai et al , 2010; Wahome et al , 2010).…”