2. Academic Validation
  3. High affinity CXCR4 inhibitors generated by linking low affinity peptides

High affinity CXCR4 inhibitors generated by linking low affinity peptides

  • Eur J Med Chem. 2019 Jun 15;172:174-185. doi: 10.1016/j.ejmech.2019.03.056.
Chaozai Zhang 1,  Lina S Huang 2,  Ruohan Zhu 3,  Qian Meng 3,  Siyu Zhu 4,  Yan Xu 3,  Huijun Zhang 4,  Xiong Fang 3,  Xingquan Zhang 5,  Jiao Zhou 6,  Robert T Schooley 5,  Xiaohong Yang 7,  Ziwei Huang 8,  Jing An 9
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA; School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China.
  • 2 Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA; College of Arts and Sciences, Cornell University, Ithaca, NY, 14853, USA.
  • 3 School of Life Sciences, Tsinghua University, Beijing, China.
  • 4 Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA; School of Life Sciences, Tsinghua University, Beijing, China.
  • 5 Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
  • 6 Nobel Institute of Biomedicine, Zhuhai, Guangdong, China.
  • 7 School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China. Electronic address: xiaohongyang88@126.com.
  • 8 Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA. Electronic address: zhuang@ucsd.edu.
  • 9 Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA. Electronic address: jan@ucsd.edu.
PMID: 30978562 DOI: 10.1016/j.ejmech.2019.03.056
Abstract

G-protein coupled receptors (GPCRs) are implicated in many diseases and attractive targets for drug discovery. Peptide Fragments derived from protein ligands of GPCRs are commonly used as probes of GPCR function and as leads for drug development. However, these Peptide Fragments lack the structural integrity of their parent full-length protein ligands and often show low receptor affinity, which limits their research and therapeutic values. It remains a challenge to efficiently generate high affinity peptide inhibitors of GPCRs. We have investigated a combinational approach involving the synthetic covalent linkage of two low affinity Peptide Fragments to determine if the strategy can yield high affinity GPCR inhibitors. We examined this design approach using the Chemokine Receptor CXCR4 as a model of GPCR system. Here, we provide a proof of concept demonstration by designing and synthesizing two Peptides, AR5 and AR6, that combine a peptide fragment derived from two viral ligands of CXCR4, vMIP-II and HIV-1 envelope glycoprotein gp120. AR5 and AR6 display nanomolar binding affinity, in contrast to the weak micromolar CXCR4 binding of each peptide fragment alone, and inhibit HIV-1 entry via CXCR4. Further studies were carried out for the representative peptide AR6 using western blotting and site-directed mutagenesis in conjunction with molecular dynamic simulation and binding free energy calculation to determine how the peptide interacts with CXCR4 and inhibits its downstream signaling. These results demonstrate that this combinational approach is effective for generating nanomolar active inhibitors of CXCR4 and may be applicable to other GPCRs.

Keywords

CXCR4; Chemokine receptor; Drug design; GPCR; HIV-1; Peptide inhibitors.

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