Targeting SDF-1/CXCL12 with a Ligand That Prevents Activation of CXCR4 through Structure-Based Drug Design

摘要

Chemokines are a family of small secreted proteins thatnorchestrate cell migration by activating a set of G-protein-couplednreceptors (GPCRs). The immune system relies on chemokinensignaling to direct lymphocyte homing, orchestrate inflammatorynresponses, and stimulate wound healing.1 Outside of these normalnfunctions, chemokines and their receptors also participate innnumerous disease states, including HIV/AIDS, asthma, autoimmunendiseases, and cancer.2,3 Most drug discovery research is directednat GPCRs,4 and therapeutic modulation of chemokine signaling isncorrespondingly directed at the receptors rather than the ligands.nSmall-molecule antagonists targeting chemokine receptors are innvarious stages of development; the HIV entry inhibitor Maraviroc,nwhich blocks the CCR5 coreceptor, was recently approved by thenFDA for clinical use.5 Chemokine variants and peptidomimeticsnare also viewed as potential inhibitors.6