Cell biology

Haematopoiesis

Biotechnology

Biology

Chemokine

Stem cell

Receptor

Agonist

Biochemistry

CXCR4

Genetics

In vivo

Progenitor cell

Pharmacology

Chemokine receptor

Rational design

Chemistry

Letters in Drug Design & Discovery

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

Rational Design of Chemokine SDF-1 Analogs with Agonist Activity for the CXCR4 Receptor and the Capacity to Rapidly Mobilize PMN and Hematopoietic Progenitor Cells in Mice