Hematopoietic growth factor mimetics.
Hematopoietic growth factors are glycoproteins of 15-70 kDa. Although much clinical success has been obtained using recombinant proteins produced in mammalian cell lines and in microbial fermentation processes, the full-length polypeptides necessarily are expensive to produce, require parenteral administration, and in some cases have provoked detrimental immune responses. With the availability of high throughput biological function and receptor binding assays it has become possible to screen millions, if not billions, of randomly produced organic compounds and relatively short peptides to identify lead compounds for the development of small molecular mimetics of hematopoietic growth factors. Herein the strategies used to screen libraries of small molecules and peptides and the successes in finding mimetics and antagonists for/to erythropoietin, granulocyte colony-stimulating factor, and thrombopoietin are reviewed. Finally, the structural study of mimetic-receptor complexes has provided us with many molecular details of growth factor-induced receptor activation and is likely to yield new insights into the molecular basis of hematopoietic signal transduction.
Kaushansky
K
K
Division of Hematology, University of Washington School of Medicine, Seattle, Washington 98195, USA. kkaushan@u.washington.edu
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001435:Bacteriophages; D001667:Binding, Competitive; D019281:Dimerization; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004921:Erythropoietin / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000187:drug effects; D011817:Rabbits; D018121:Receptors, Cytokine; D017467:Receptors, Erythropoietin / Q000187:drug effects; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects; D053628:Receptors, Thrombopoietin; D017701:Reticulocyte Count; D013329:Structure-Activity Relationship; D013926:Thrombopoietin / Q000737:chemistry / Q000494:pharmacology
C099963:EPO mimetic peptide 1; C400968:GW395058; D016298:Hematopoietic Cell Growth Factors; D009363:Neoplasm Proteins; D019151:Peptide Library; D010455:Peptides; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D017467:Receptors, Erythropoietin; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D053628:Receptors, Thrombopoietin; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; C082218:MPL protein, human; D013926:Thrombopoietin