Anadys Pharmaceuticals, Inc.

Scriptgen Pharmaceuticals, Inc.

Anadys Pharmaceutical, Inc.

Andrew A Pakula

Jaime E Arenas

James W Lillie

Lance Gavin Laing

Sharon T Cload

James U Bowie

Alan Franklin Corin

Julianne Bryan

The present invention provides methods for screening for bioactive compounds, in particular those that bind to RNA sequences involved in the pathogenesis of disease or in regulation of a physiological function. The methods involve assessing the stability and/or the conformation of an RNA target in the presence and absence of test ligands, and identifying as a ligand any test ligand that causes a measurable change in target RNA stability and/or conformation. In a preferred embodiment, the effect of a ligand on target RNA stability and/or conformation is assessed by measuring the fluorescence polarization of a fluorescently labeled probe.

Screen employing fluorescence anisotropy to identify compounds with affinity for nucleic acids

The present invention provides methods for high-throughput screening for bioactive compounds, in particular those that bind to RNA sequences involved in the pathogenesis of disease or in regulation of a physiological function. The methods involve measuring the conformation of an RNA target in the presence and absence of test ligands, and identifying as a ligand any test ligand that causes a measurable change in target RNA conformation.

Screen for compounds with affinity for nucleic acids

The present invention is directed to a method for selecting compounds for use in treating sickle cell disease in a patient. The method comprises the steps of selecting a first set of HbS ligands from a first group of chemical compounds, selecting from the first set of HbS ligands a seconds set that exhibit inhibition of HbS polymerization, and selecting from the second set a third set that display anti-sickling activity of red blood cells when in the presence thereof. The method may include the step of performing a methemoglobin S proteolysis assay measuring a percent protease protection for each compound. The method may additionally include the steps of measuring HbS aggregation, inhibition of protease, deoxy-HbS gelation inhibition activity, O,affinity of HbS, and cytotoxic effect to cell activity. The method may further include assessing red blood cell morphology, and eliminating compounds that contain moieties that bind to heme. The steps of the method may be repeated on analogs of compounds that are selected using one or more steps of the method. The present invention also includes a method of treating sickle cell disease in a patient, which comprises administering to the patient a pharmaceutical formulation including a selected concentration of an HbS ligand and a pharmaceutically acceptable carrier therefore. The HbS ligand, which may be an isoquinolium derivative, is one exhibiting inhibition of HbS polymerization and displaying anti-sickling activity of red blood cells when in the presence thereof.

Anti-sickling agents: selection methods and effective compounds

A novel method for screening chemical compounds, test ligands, for potential pharmaceutical effectiveness. The disclosed method identifies possible therapeutic test ligands by placing them in the presence of target proteins and determining the ability of test ligands to increase the ratio of folded target protein to unfolded target protein. This differs significantly from known methods of novel pharmaceutical testing in that the biochemical function of the target protein need not be known and, except for one of the five embodiments of the method, the existence of any known ligands of the target protein is unnecessary.

Growing community of inventors

Lexington, MA, United States of America

Andrew A Pakula