Structure-based design and characterization of novel platforms for ricin and shiga toxin inhibition.
Ribosome inhibiting proteins, RIPs, are a widespread family of toxic enzymes. Ricin is a plant toxin used as a poison and biological warfare agent; shiga toxin is a homologue expressed by pathogenic strains of E. coli. There is interest in creating effective antidote inhibitors to this class of enzymes. RIPs act by binding and hydrolyzing a specific adenine base from rRNA. Previous virtual screens revealed that pterins could bind in the specificity pocket of ricin and inhibit the enzyme. In this paper we explore a range of compounds that could serve as better platforms for inhibitor design. This establishes the importance of key hydrogen bond donors and acceptors for active-site complementarity. 8-Methyl-9-oxoguanine is a soluble compound that has the best inhibitory properties of any platform tested. The X-ray structure of this complex revealed that the inhibitor binds in an unexpected way that provides insight for future design. Several inhibitors of ricin were also shown to be inhibitors of shiga toxin, suggesting this program has the potential to develop effective antidotes to an important form of food poisoning.
Miller
Darcie J
DJ
Department of Chemistry and Biochemistry and Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, Texas 778712, USA.
Ravikumar
Kabyadi
K
Shen
Huafeng
H
Suh
Jung-Keun
JK
Kerwin
Sean M
SM
Robertus
Jon D
JD
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006147:Guanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D012276:Ricin / Q000037:antagonists & inhibitors / Q000737:chemistry*; D022621:Shiga Toxin / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012995:Solubility
D004791:Enzyme Inhibitors; D011743:Pyrimidines; D006147:Guanine; D022621:Shiga Toxin; D012276:Ricin