High-affinity small molecule formylpeptide receptor ligands from screening of combinatorial mixture-based libraries
AssigneesStc.Unm, Torrey Pines Institute for Molecular Studies
InventorsBruce S. Edwards, Larry A. Sklar, Clemencia Pinilla, Richard A. Houghten, Jon R. Appel, Marc A. Giulianotti, Jose Medina-Franco
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Abstract
The present invention provides novel methods and assays for high-throughput screening of combinatorial libraries to identify FPR1 and/or FPR2 ligands (e.g., agonists and/or antagonists), preferably FPR1 agonists and/or FPR2 antagonists, by positional scanning deconvolution. The invention also provides novel FPR1 and FPR2 ligands (e.g, agonists and antagonists), related pharmaceutical compositions and methods of treating FPR1 and FPR2-related disorders.
Claims34
A high throughput assay for screening for FPR1 ligands and FPR2 ligands using positional scanning deconvolution, the assay comprising mixture-based combinatorial libraries and a single cross-reactive peptide ligand for a duplex flow cytometric screen of levels of FPR1 and/or FPR2 expression in color-coded cell lines.
A method for high throughput screening of combinatorial libraries to identify a FPR1 and/or FPR2 ligand, the method comprising conducting positional scanning deconvolution of a plurality of mixture-based combinatorial libraries using a single cross-reactive peptide ligand and a duplex flow cytometric screen that identifies levels of FPR1 and/or FPR2 expression in color-coded cell lines.
A compound as set forth in FIG. 1EX3, FIG. 1EX4, FIG. 2EX5 or FIG. 2EX8 herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.
A method of modulating FPR1 or FPR2 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as set forth in FIG. 1EX3, FIG. 1EX4, FIG. 2EX5 or FIG. 2EX8 herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.
A method for high-throughput screening of combinatorial libraries to identify a FPR1 and/or FPR2 ligand, the method comprising conducting positional scanning deconvolution of a plurality of mixture-based combinatorial libraries using a single cross-reactive peptide ligand and a duplex flow cytometric screen that identifies levels of FPR1 and/or FPR2 expression in color-coded cell lines, wherein the step of positional scanning deconvolution uses dual-activity difference (DAD) maps to (a) represent a visual and quantitative analysis of all pair-wise comparisons of one or more substitutions around a putative FPR1 ligand and/or a FPR2 ligand, and (b) to identify putative FPR1 ligand and/or a FPR2 ligand single- and double-target R-cliffs.
A compound selected from the group consisting of:
- and
- and the pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates and polymorphs of the compound.
Dependencies are inferred from the claim text.