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

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.