Cyclotides as tools in chemical biology

de Veer, Simon J. , Weidmann, Joachim and Craik, David J. (2017) Cyclotides as tools in chemical biology. Accounts of Chemical Research, 50 7: 1557-1565. doi:10.1021/acs.accounts.7b00157


Author de Veer, Simon J.
Weidmann, Joachim
Craik, David J.
Title Cyclotides as tools in chemical biology
Journal name Accounts of Chemical Research   Check publisher's open access policy
ISSN 0001-4842
1520-4898
Publication date 2017-06-23
Year available 2017
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1021/acs.accounts.7b00157
Open Access Status Not yet assessed
Volume 50
Issue 7
Start page 1557
End page 1565
Total pages 9
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Subject 1600 Chemistry
Abstract ConspectusAmong the various molecules that plants produce for defense against pests and pathogens, cyclotides stand out as exceptionally stable and structurally unique. These ribosomally synthesized peptides are around 30 amino acids in size, and are stabilized by a head-to-tail cyclic peptide backbone and three disulfide bonds that form a cystine knot. They occur in certain plants of the Rubiaceae, Violaceae, Cucurbitaceae, Fabaceae, and Solanaceae families, with an individual plant producing up to hundreds of different cyclotides. Aside from being exploitable as crop protection agents based on their natural pesticidal activities, cyclotides are amenable to repurposing by chemists for use as drug leads or as tools in chemical biology. Their macrocyclic peptide backbone and knotted arrangement of three disulfide bonds engenders cyclotides with resistance to proteolytic degradation, high temperatures, and chemical chaotropes. Furthermore, their small size makes them accessible to synthesis using solid-phase peptide chemistry and so non-natural cyclotides can be designed and synthesized for a variety of applications. Our focus here is on cyclotides as tools in chemical biology, and there are four main areas of application that have appeared in the literature so far: (i) cyclotides as probes of membrane binding; (ii) cyclotides as probes of biosynthetic pathways for peptide cyclization; (iii) cyclotides as probes of protease specificity and function; and (iv) cyclotides as probes of receptor binding and specificity, with the potential for them to be developed as drug leads. The main methods used in these studies include solid-phase peptide chemistry for synthesis and NMR spectroscopy for structural characterization, as well as a wide range of biochemical and biophysical techniques for probing intermolecular interactions. In addition, cyclotides have been examined in diverse biological assays, ranging from enzyme inhibition to cell penetration, intracellular targeting and cytotoxicity. The main finding to have emerged from studies over the past decade is that cyclotides are exceptionally stable under a variety of conditions (in assay buffers, biological fluids, membranes, and recombinant expression systems). Furthermore, they are structurally very well-defined and amenable to sequence substitutions that can introduce new desired biological activities, generally without compromising their exceptional stability. Both features contribute to their use as peptide-based frameworks in drug design. Finally, they occupy a size niche between traditional small-molecule drugs (<500 Da in molecular weight) and protein-based biologics (>5000 Da) and thus can probe receptors, membranes, and protein-protein interactions in different ways to what is possible with either small molecules or biologics. Overall, cyclotides are an exciting class of peptides that have great potential as ultrastable chemical biology probes in a variety of applications. They have the advantage of specificity (typical of proteins) combined with the synthetic accessibility of small molecules.
Keyword Chemistry, Multidisciplinary
Chemistry
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1107403
DP150100443
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 12 Sep 2017, 11:48:39 EST by Simon De Veer on behalf of Institute for Molecular Bioscience