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

Journal of Medicinal Chemistry (Impact Factor: 5.45). 11/2012; 55(23). DOI: 10.1021/jm301468k
Source: PubMed


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 ≈ 20 nM) and an efficient HIV-1 cell-entry blocker (EC50 ≈ 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 anti-cancer and anti-HIV-1 therapeutics.

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Available from: Julio A Camarero, Jan 16, 2015
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    • "In summary we report here for the first time the design and synthesis of a novel cyclotide able to efficiently activate the MAS1 receptor. This was successfully accomplished by grafting an AT1-7-derived peptide onto loop 6 of the cyclotide MCoTI-I using the side-chains of the first and last residues of the grafted peptide through the formation of isopeptide bonds (Figure 1). 1 H-NMR studies also revealed that the grafting of the AT1-7-derived peptide using isopeptide bonds onto this loop did not affect the native cyclotide scaffold, indicating the tolerance of this loop for the grafting of peptide sequences using non-native peptide bonds[18,20]. Cyclotide MCo-AT1-7 showed to be a potent MAS1 agonist, with similar activity to that of the peptide AT1-7. It is also worth noting that the cyclotide MCo-AT1-7 showed a remarkable resistance to biological degradation in human serum, with a τ 1/2 value of «39 h. "
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    ABSTRACT: We report for the first time the design and synthesis of a novel cyclotide able to activate the unique receptor of angiotensin (1-7) (AT1-7), the MAS1 receptor. This was accomplished by grafting an AT1-7 peptide analog onto loop 6 of cyclotide MCoTI-I using isopeptide bonds to preserve the α-amino and C-terminal carboxylate groups of AT1-7, which are required for activity. The resulting cyclotide construct was able to adopt a cyclotide-like conformation and showed similar activity to that of AT1-7. 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 in the treatment of cancer and myocardial infarction.
    Preview · Article · Jan 2016 · Molecules
    • "Cyclotides are plant proteins with a structural scaffold incorporating six conserved cysteines that form a cystine-knot motif (Craik et al., 1999; Gruber et al., 2008; G€ oransson et al., 2012) (Fig. 1). They have attracted much attention for their pharmaceutical activities, including uterotonic, anthelmintic and antihuman immunodeficiency virus (anti-HIV) effects, and as scaffolds for drug design owing to their exceptional stability, but their relevance to plant physiology, ecology and evolution remains largely unexplored (Gustafson et al., 1994; Gran et al., 2000; Colgrave et al., 2008; Aboye et al., 2012; Craik et al., 2012; Koehbach et al., 2013). One or multiple cyclotide domains are encoded in divergent gene structures that occur sporadically across five angiosperm families, suggesting that cyclotides probably originated by convergent evolution (Gruber et al., 2008; Camarero, 2011; Nguyen et al., 2011, 2013; Poth et al., 2011a,b; Mylne et al., 2012) (Fig. 1). "
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    ABSTRACT: Plants have evolved many strategies to protect themselves from attack, including peptide toxins that are ribosomally synthesized and thus adaptable directly by genetic polymorphisms. Certain toxins in Clitoria ternatea (butterfly pea) are cyclic cystine-knot peptides of c. 30 residues, called cyclotides, which have co-opted the plant's albumin-1 gene family for their production. How butterfly pea albumin-1 genes were commandeered and how these cyclotides are utilized in defence remain unclear. The role of cyclotides in host plant ecology and biotechnological applications requires exploration. We characterized the sequence diversity and expression dynamics of precursor and processing proteins implicated in butterfly pea cyclotide biosynthesis by expression profiling through RNA-sequencing (RNA-seq). Peptide-enriched extracts from various organs were tested for activity against insect-like membranes and the model nematode Caenorhabditis elegans. We found that the evolution and deployment of cyclotides involved their diversification to exhibit different chemical properties and expression between organs facing different defensive challenges. Cyclotide-enriched fractions from soil-contacting organs were effective at killing nematodes, whereas similar enriched fractions from aerial organs contained cyclotides that exhibited stronger interactions with insect-like membrane lipids. Cyclotides are employed as versatile and combinatorial mediators of defence in C. ternatea and have specialized to affect different classes of attacking organisms.
    No preview · Article · Dec 2015 · New Phytologist
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    • "As both peptides have the ability to enter cells (Greenwood et al. 2007; Cascales et al. 2011; Contreras et al. 2011; D'Souza et al. 2014), they have been touted as potential vectors for the delivery of grafted epitopes with desired activities to intracellular targets (Ji et al. 2013). Examples of grafting applications include engineering of: (i) MCoTI-I into an anti-HIV agent (Aboye et al. 2012) and an antagonist of intracellular proteins Hdm2 and HdmX for suppressing tumor growth (Ji et al. 2013) and (ii) MCoTI-II into a β-tryptase inhibitor (Thongyoo et al. 2009; Sommerhoff et al. 2010) and human leukocyte elastase inhibitor (Thongyoo et al. 2009) for inflammatory disorders, and a pro-angiogenic agent for wound healing (Chan et al. 2011). Despite these remarkable successes, the introduction of new activities onto the Momordica cyclic peptide scaffold remains challenging because the limiting structural and functional constraints are not yet fully understood. "
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    ABSTRACT: Cyclic proteins have evolved for millions of years across all kingdoms of life to confer structural stability over their acyclic counterparts while maintaining intrinsic functional properties. Here, we show that cyclic miniproteins (or peptides) from Momordica (Cucurbitaceae) seeds evolved in species that diverged from an African ancestor around 19 Ma. The ability to achieve head-to-tail cyclization of Momordica cyclic peptides appears to have been acquired through a series of mutations in their acyclic precursor coding sequences following recent and independent gene expansion event(s). Evolutionary analysis of Momordica cyclic peptides reveals sites that are under selection, highlighting residues that are presumably constrained for maintaining their function as potent trypsin inhibitors. Molecular dynamics of Momordica cyclic peptides in complex with trypsin reveals site-specific residues involved in target binding. In a broader context, this study provides a basis for selecting Momordica species to further investigate the biosynthesis of the cyclic peptides and for constructing libraries that may be screened against evolutionarily related serine proteases implicated in human diseases.
    Full-text · Article · Nov 2014 · Molecular Biology and Evolution
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