Hanes Melinda S, Salanga Catherina L, Chowdry Arnab B, Comerford Iain, McColl Shaun R, Kufareva Irina, Handel Tracy M
From the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093 and.
Chemokine Biology Group, The School of Molecular and Biomedical Science, The University of Adelaide, North Terrace Campus, Adelaide, South Australia 5005, Australia.
J Biol Chem. 2015 Sep 11;290(37):22385-97. doi: 10.1074/jbc.M115.675108. Epub 2015 Jul 27.
The chemokine CXCL12 and its G protein-coupled receptors CXCR4 and ACKR3 are implicated in cancer and inflammatory and autoimmune disorders and are targets of numerous antagonist discovery efforts. Here, we describe a series of novel, high affinity CXCL12-based modulators of CXCR4 and ACKR3 generated by selection of N-terminal CXCL12 phage libraries on live cells expressing the receptors. Twelve of 13 characterized CXCL12 variants are full CXCR4 antagonists, and four have Kd values <5 nm. The new variants also showed high affinity for ACKR3. The variant with the highest affinity for CXCR4, LGGG-CXCL12, showed efficacy in a murine model for multiple sclerosis, demonstrating translational potential. Molecular modeling was used to elucidate the structural basis of binding and antagonism of selected variants and to guide future designs. Together, this work represents an important step toward the development of therapeutics targeting CXCR4 and ACKR3.
趋化因子CXCL12及其G蛋白偶联受体CXCR4和ACKR3与癌症、炎症及自身免疫性疾病相关，是众多拮抗剂研发工作的靶点。在此，我们描述了一系列基于CXCL12的新型、高亲和力CXCR4和ACKR3调节剂，这些调节剂是通过在表达受体的活细胞上筛选N端CXCL12噬菌体文库产生的。13个已表征的CXCL12变体中有12个是完全CXCR4拮抗剂，4个的解离常数（Kd）值<5纳米。新变体对ACKR3也显示出高亲和力。对CXCR4亲和力最高的变体LGGG-CXCL12在小鼠多发性硬化症模型中显示出疗效，证明了其转化潜力。分子建模用于阐明所选变体结合和拮抗的结构基础，并指导未来设计。总之，这项工作是开发靶向CXCR4和ACKR3疗法的重要一步。
