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Cyclotides as natural anti‐HIV agents
Author(s) -
Ireland David C.,
Wang Conan K. L.,
Wilson Jennifer A.,
Gustafson Kirk R.,
Craik David J.
Publication year - 2008
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.20886
Subject(s) - chemistry , subfamily , computational biology , human immunodeficiency virus (hiv) , structural motif , peptide , drug discovery , combinatorial chemistry , biochemistry , biology , virology , gene
Cyclotides are disulfide rich macrocyclic plant peptides that are defined by their unique topology in which a head‐to‐tail cyclized backbone is knotted by the interlocking arrangement of three disulfide bonds. This cyclic cystine knot motif gives the cyclotides exceptional resistance to thermal, chemical, or enzymatic degradation. Over 100 cyclotides have been reported and display a variety of biological activities, including a cytoprotective effect against HIV infected cells. It has been hypothesized that cyclotides from one subfamily, the Möbius subfamily, may be more appropriate than bracelet cyclotides as drug candidates given their lower toxicity to uninfected cells. Here, we report the anti‐HIV and cytotoxic effects of three cyclotides, including two from the Möbius subfamily. We show that Möbius cyclotides have comparable inhibitory activity against HIV infection to bracelet cyclotides and that they are generally less cytotoxic to the target cells. To explore the structure activity relationships (SARs) of the 29 cyclotides tested so far for anti‐HIV activity, we modeled the structures of the 21 cyclotides whose structures have not been previously solved. We show that within cyclotide subfamilies there is a correlation between hydrophobicity of certain loop regions and HIV inhibition. We also show that charged residues in these loops impact on the activity of the cyclotides, presumably by modulating membrane binding. In addition to providing new SAR data, this report is a mini‐review that collates all cyclotide anti‐HIV information reported so far and provides a resource for future studies on the therapeutic potential of cyclotides as natural anti‐HIV agents. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 51–60, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com