Exploratory Studies on Development of the Chemokine Receptor CXCR4 Antagonists toward Downsizing

Hirokazu Tamamura,Hiroshi Tsutsumi,Wataru Nomura,Nobutaka Fujii

doi:10.4137/pmc.s422

Hirokazu Tamamura, Hiroshi Tsutsumi + Show 2 more

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https://doi.org/10.4137/pmc.s422

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Abstract

Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry. The chemokine receptor CXCR4 is a GPCR that possesses a unique ligand CXCL12/stromal cell-derived factor-1 (SDF-1). The interaction between CXCL12 and CXCR4 is essential for the migration of progenitor cells during embryonic development of the cardiovascular, hemopoietic and central nervous systems, and also involved in several intractable disease processes, including HIV infection, cancer cell metastasis, progression of acute and chronic leukemias, rheumatoid arthritis and pulmonary fibrosis. Thus, CXCR4 may be an important therapeutic target in all of these diseases, and various CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists. This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing.

Highlights

As a postgenome project, proteomics has been prosperous in life science, and selective ligands involving protein networks have been valuable and useful for studies on chemical biology
We evaluated the inhibitory activity of our T140 analogs against the migration of breast cancer cells in vitro and metastasis of breast cancer cells in vivo (Tamamura, Hori et al 2003)
We have found strong anti-HIV agents, T22 and its downsized analog T140, identified as entry inhibitors that bind to the chemokine receptor CXCR4 and inhibit entry of X4-HIV1 to T-cells

Summary

Introduction

Proteomics has been prosperous in life science, and selective ligands involving protein networks have been valuable and useful for studies on chemical biology. For downsizing of T140 analogs, a pharmacophore-guided approach was performed using cyclic pentapeptide libraries, which were composed of two L/D-Arg, L/D-Nal and L/D-Tyr in addition to Gly as a spacer This approach led to FC131 [cyclo(-Arg1-Arg2Nal3-Gly4-D-Tyr5-)], which showed strong CXCR4-antagonistic activity comparable to that of T140 (Fig. 3) (Fujii et al 2003). Since a second Arg residue is thought to be indispensable for high potency and an aromatic residue [L/D-Phe(4-F)] has been incorporated into position 1, four analogs [L/D-Phe(4-F), L/D-Arg5]-FC131 were synthesized based on replacement of D-Tyr by L/D-Arg5 Among these analogs, FC602, which is [D-Phe(4F), Arg5]-FC131, shows the most potent activity, which is 10-fold greater than that of [D-Tyr, Arg5]FC131 (Fig. 3). FC602 is a novel lead, which involves a pharmacophore moiety different from the pharmacophore groups of FC131

A Linear Type of Low Molecular Weight CXCR4 Antagonists

Conclusion