title: Dinucleosides with non-natural backbones: a new class of ribonuclease A and angiogenin inhibitors.
abstract: Ribonuclease A (RNase A) serves as a convenient model enzyme in the identification and development of inhibitors of proteins that are members of the ribonuclease superfamily. This is principally because the biological activity of these proteins, such as angiogenin, is linked to their catalytic ribonucleolytic activity. In an attempt to inhibit the biological activity of angiogenin, which involves new blood vessel formation, we employed different dinucleosides with varied non-natural backbones. These compounds were synthesized by coupling aminonucleosides with dicarboxylic acids and amino- and carboxynucleosides with an amino acid. These molecules show competitive inhibition with inhibition constant (K(i)) values of (59±3) and (155±5) μM for RNase A. The compounds were also found to inhibit angiogenin in a competitive fashion with corresponding K(i) values in the micromolar range. The presence of an additional polar group attached to the backbone of dinucleosides was found to be responsible for the tight binding with both proteins. The specificity of different ribonucleolytic subsites were found to be altered because of the incorporation of a non-natural backbone in between the two nucleosidic moieties. In spite of the replacement of the phosphate group by non-natural linkers, these molecules were found to selectively interact with the ribonucleolytic site residues of angiogenin, whereas the cell binding site and nuclear translocation site residues remain unperturbed. Docked conformations of the synthesized compounds with RNase A and angiogenin suggest a binding preference for the thymine-adenine pair over the thymine-thymine pair.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee, 847 Monroe, Johnson Bldg, Room 331, Memphis, Tennessee 38163, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Debnath
authors.forename: Swagata
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Tanmaya
authors.initials: T
authors.lastname: Pathak
mesh_terms: D000818:Animals; D002417:Cattle; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D017382:Reactive Oxygen Species; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors*
chemical_list: D009705:Nucleosides; D017382:Reactive Oxygen Species; C046366:angiogenin; D012259:Ribonuclease, Pancreatic