Design of a Novel Cyclotide-Based CXCR4 Antagonist with Anti-Human Immunodeficiency Virus (HIV)-1 Activity

被引：108

作者：

Aboye, Teshome L. ^{[1
]}

Ha, Helen ^{[1
]}

Majumder, Subhabrata ^{[3
]}

Christ, Frauke ^{[4
,5
]}

Debyser, Zeger ^{[4
,5
]}

Shekhtman, Alexander ^{[3
]}

Neamati, Nouri ^{[1
]}

Camarero, Julio A. ^{[1
,2
]}

机构：

[1] Univ So Calif, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90033 USA

[2] Univ So Calif, Dept Chem, Los Angeles, CA 90033 USA

[3] SUNY Albany, Dept Chem, Albany, NY 12222 USA

[4] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Flanders, Belgium

[5] IRC Kulak, Flanders, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 23期

基金：

美国国家卫生研究院;

关键词：

CHEMOKINE RECEPTOR CXCR4; BONE-MARROW; MOMORDICA-COCHINCHINENSIS; HEMATOPOIETIC PROGENITOR; SCANNING MUTAGENESIS; DRUG DISCOVERY; SMALL-MOLECULE; HIV ACTIVITY; PEPTIDE; MOBILIZATION;

D O I：

10.1021/jm301468k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein, we report for the first time the design and synthesis of a novel cyclotide able to efficiently inhibit HIV-1 viral replication by selectively targeting cytokine receptor CXCR4. This was accomplished by grafting a series of topologically modified CVX15 based peptides onto the loop 6 of cyclotide MCoTI-I. The most active compound produced in this study was a potent CXCR4 antagonist (EC50 approximate to 20 nM) and an efficient HIV-1 cell-entry blocker (EC50 approximate to 2 nM). This cyclotide also showed high stability in human serum, thereby providing a promising lead compound for the design of a novel type of peptide-based anticancer and anti-HIV-1 therapeutics.

引用

页码：10729 / 10734

页数：6

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