We designed SDF-1α / CXCL12 (1) analogs to improve in vivo bioactivity. A linear analogue (2) consisting of AA1-14 of (1) joined by (Gly)4 to AA56-67 binds CXCR4, but with ∼100-fold less affinity. Cyclized analogs (3) and (4) were 2-3-fold more active. Substitution of the cysteines in analog (3) forming analog (5) prevented dimerization and increased plasma stability. Analogs (3) and (5) rapidly mobilized neutrophils and hematopoietic progenitor cells and synergized with G-CSF in normal mice.
Keywords: agonist peptides, stem cell mobilization, hematopoiesis, cxcr4, rational design
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