Oxytocic plant cyclotides as templates for peptide g proteincoupled receptor ligand design johannes koehbach,a margaret obrien,b markus muttenthaler,c marion miazzo,a muharrem akcan,d alysha g. Accordingly, they have been proposed as templates to stabilize bioactive epitopes in drugdesign applications. The ultrastable cyclotides are promising templates for drug. Therefore, they are larger and more bulky than the nonapeptide ligands oxytocin and vasopressin. Cyclotide mcotii has been successfully used for the design of potent antagonists for the cytokine receptor cxcr4. Immunolocalization of cyclotides in plant cells, tissues and organ supports.
This article gives a brief overview of the role of nmr in drug design and illustrates this role with examples studied in our laboratory in recent years on disulfiderich peptides. Toxic effects of cyclotides, whose native function is as insecticidal agents, can be removed by simple mutagenesis, thus rationalizing the apparent conundrum of proposing insecticidal agents as. Nuclear magnetic resonance spectroscopy nmr is a powerful technique for determining the structures, dynamics and interactions of molecules, and the derived information can be useful in drug design applications. Discovery, structure and biological activities of the cyclotides. Native cyclotides can be extracted in good yield from plants, but the ability to synthesize modi.
David j craik, university of queensland, brisbane, australia, whose laboratory is working over 20 years in the field, summarizes the history of cyclotides. Analysis of cyclotides in viola ignobilis by nano liquid. Nature offers an abundance of compounds for drug discovery. Their natural role is thought to be as plant defence agents, most notably against insect pests, but they also have potential applications in drug design and agriculture. Design of a cyclotide antagonist of neuropilin1 and 2.
Given a protein structure, andor its binding site, andor its active ligand possibly bound to protein, find a new molecule that changes the proteins activity hiv protease inhibitor example courte sy of bill welsh structurebased drug design ligandbased drug design. Cyclotides represent a new class of natural plant compounds, which could be considered ideal template molecules for drug design. Dissecting the oxidative folding of circular cystine knot. Gpcrs and ii cyclotides can serve as a template for the design of new classes of gpcr ligands, thus opening new avenues for cyclotidebased drug development. Toxic effects of cyclotides, whose native function is as insecticidal agents, can be removed by simple mutagenesis, thus rationalizing the apparent conundrum of proposing insecticidal agents as leads for human therapeutics. Cyclotides are disulfiderich proteins from plants that are characterized by a unique combination of a headtotail cyclized backbone and a knotted arrangement of three conserved disulfide bonds. Cyclotides have been also shown to fold inside bacterial cells 19, 20, which have a more reductive cytosolic environment than eukaryotic cells and therefore is highly unlikely that they were reduced in the cytosol of mammalian cells. The drug should have a good selectivity for its target 2.
European journal of medicinal chemistry 2014, 77, 248257. Apr 22, 2014 read disulfiderich macrocyclic peptides as templates in drug design, european journal of medicinal chemistry on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Oxytocic plant cyclotides as templates for peptide g. They are extremely stable and have a range of bioactivities including antihiv and insecticidal activity. Cyclotides suppress human tlymphocyte proliferation by an interleukin 2dependent mechanism. Cyclotides as grafting frameworks for protein engineering and. Cyclotides are remarkably stable proteins from plants that have a range of pharmaceutical and agricultural applications based on both their various bioactivities. This article identifies gaps in current knowledge on cyclotides. Computational design of hypothetical new peptides based on a cyclotide. In this family, 6 conserved cysteine residues are involved. For example, engineered cyclotides can have high oral bioavailability that is comparable to small molecule drugs while retaining desired target specificity of the grafted epitopes 69. The results showed that antibacterial effects of cyclotides were constant after 1, 2 and 3 months fig. The cyclotides are potent insecticides inhibiting the growth of insect larvae this site is dedicated to the study of a fascinating new class of plant proteins called the cyclotides.
Cyclotides are plant proteins with exceptional stability owing to the presence of a cyclic backbone and three disulfide bonds arranged in a cystine knot motif. Altogether, these characteristics make them promising leads or frameworks for peptide drug design 4, 31, 32. Circular plant peptides as templates for gpcr drug. Design of a mcotibased cyclotide with angiotensin 17like. Computational design of hypothetical new peptides based on a. Disulfiderich macrocyclic peptides as templates in drug. Their natural function in plants seems to be as hostdefense agents, as deduced from their potent insecticidal activity and their high expression levels in many plant tissues 2, 3. Discovery, structure and biological activities of cyclotides. These recently characterised molecules found in plants of the rubiaceae and violaceae families are small disulfiderich proteins that have the unusual feature of a cyclic backbone hence the name cyclic peptides. These recently characterised molecules found in plants of the rubiaceae and violaceae families are small disulfiderich proteins that have the unusual feature of a. Cyclotides as templates in drug design request pdf researchgate.
Read disulfiderich macrocyclic peptides as templates in drug design, european journal of medicinal chemistry on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. First report of a cyclotidepenetrating cells and opens up the possibility of using cyclotides as drugdesign scaffolds for intracellular targets. Studies in our laboratory on cyclotides are supported by grants from the australian research council dp0880105 and the. Best strategy structurebased drug design coupled with. Request pdf cyclotides as templates in drug design cyclotides are remarkably stable proteins from plants that have a range of pharmaceutical and.
Oxytocic plant cyclotides as templates for peptide g protein. Harvey,d sarah arrowsmith,f sunithi gunasekera,g terry j. Cyclotides are disulfiderich peptides from plants that are exceptionally stable as a result of their unique cyclic cystine knot structural motif. Hydrophobic aromatic hbond acceptor hbond donor cationic or anionic moieties. Because of their highly stable peptide framework they might make useful templates in drug design programs, and their insecticidal activity opens the possibility of applications in crop protection. It includes applications of cyclotides and cyclotidelike molecules as peptidebased drug leads and diagnostic agents. Because of this structure they are ultrastable and have attracted interest as peptidebased templates for drug design applications. Cyclotides as grafting frameworks for protein engineering. Strategy for the utilisation of cyclotides in drug design. An immunomodulatory cyclotide on its way to the clinic. This and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications. Given the stability of the cyclotide framework, there is interest in using these peptides as scaffolds in drug design. The ultrastable cyclotides are promising templates for drug development applications and are currently being assessed for the potential breadth of their applications.
This was accomplished by grafting an at17 peptide analog onto loop 6 of cyclotide mcotii using isopeptide bonds to preserve the. Figure 3 also highlights some of the more unusual cyclotides with longer loops and structures. Cyclotides as templates in drug design qut eprints. Accordingly, the cyclotide molecules are an attractive platform for drug design applications. Discovery, structure and biological activities of the. Cyclotides, a novel ultrastable polypeptide scaffold for drug. Toxic effects of cyclotides, whose native function is as insecticidal agents, can be removed by simple mutagenesis, thus rationalizing the apparent.
Cyclotides as templates in drug design request pdf. Results bioactivityguided fractionation of uterotonic plant cyclotides. The cyclotides are a family of cyclic peptides that range between 28 and 37 amino acid residues and are commonly found in plant species from the violaceae, rubiaceae, curcubitaceae, poaceae, and fabaceae families. Examples include reengineered cyclotides with angiogenic activity and potential wound healing properties chan et al. Oct 30, 2015 accordingly, the cyclotide molecules are an attractive platform for drug design applications. These features make cyclotides as templates for drug design applications. Cyclotides exhibit a range of activities, including insecticidal, antihiv, antimicrobial, and cytotoxic activities, and are thus of interest for applications in drug design and agriculture. Feb 21, 2012 it includes applications of cyclotides and cyclotidelike molecules as peptidebased drug leads and diagnostic agents. Thus, we used the sequence of kalata b7 as a template for the synthesis of oxytocinlike nonapeptides.
Cyclotides from the trypsin inhibitory subfamily, mainly cyclotides mcotiiii, have also been used as molecular templates to produce cyclotides with novel biological activities by employing molecular grafting see table 1. Introduction cyclotides were first defined as a unique family of proteins in 1999 1, with the name being a condensation of the terms cyclo and peptide to indicate their major dis. In terms of pharmaceutical applications of cyclotides, there are three broad. Design and therapeutic applications of cyclotides future. Pdf cyclotides as a basis for drug design researchgate. Cyclic peptides, cyclotides, drug design, insecticide, kalata b1, plant defence. The potential of the cyclotide scaffold for drug development. Comparison of the antimicrobial effects of semipurified. A set of structural features in a molecule that is recognized at a receptor site and responsible for that molecules biological activity typical features. We report for the first time the design and synthesis of a novel cyclotide able to activate the unique receptor of angiotensin 17 at17, the mas1 receptor. In precursor proteins containing multiple cyclotide domains these can either be all identical sequences, as is the case for oak4, or they can be different cyclotides as in. Cyclotides as templates in drug design sciencedirect. This stability and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications.
A wide range of pharmaceutically relevant activities have been found in screening studies of natural cyclotides craik et al. Disulfiderich macrocyclic peptides as templates in drug design. This provides a proofofprinciple for the design and development of cyclotidebased peptide ligands. Structural plasticity of the cycliccystineknot framework. Typical drug like molecules can have many thousands of local minima that must be evaluated proteins have a significantly larger accessible conformational space.
Frontiers optimization of the cyclotide framework to. Their applications as templates for the design of antiangiogenic agents for the treatment of cancer and as antiinfective agents are also described. An herbal extract that has been used for many generations by tra. Cyclotides are bioactive miniproteins from plants that have the unique topological feature of a headtotail cyclic backbone combined with a cystine knot. Henriques and craik, 2015 and numerous synthetic designer cyclotides have also been made for applications in drug design. Dec 24, 20 cyclotides as peptide templates for oxytocin and vasopressin gpcr ligand design. This cited by count includes citations to the following articles in scholar. Cyclotides have been successfully modified to incorporate a wide range of desired activities poth et al. Drug design, development and therapy volume 6 dove press.
Computational design of hypothetical new peptides based on. Discovery, structure and biological activities of cyclotides discovery, structure and biological activities of cyclotides daly, norelle l rosengren, k. Cyclotide biosynthesis involves processing from a genetically encoded. This article identifies gaps in current knowledge on cyclotides and suggests. For example, sfti1 was engineered to produce a selective inhibitor of klk4 k i 3. This site is dedicated to the study of a fascinating new class of plant proteins called the cyclotides. The potential of the cyclotide scaffold for drug development ncbi. Circular plant peptides as templates for gpcr drug discovery. Cyclotides as peptide templates for oxytocin and vasopressin gpcr ligand design.
The current drug design applications of sfti1 have significance in the field of anticancer therapeutics. Natural cyclotides target cell membranes, so understanding cyclotidemembrane interactions is useful in applying cyclotides in drug design applications. The cyclotides appear to act as defence molecules in plants jennings, et al. The drug should have a good level of activity for its target 3. This article gives a brief overview of the role of nmr in drug design and illustrates this role with examples studied in our laboratory in recent years on. The figure below shows their marked effects on growth and development of helicoverpa species fed a diet containing cyclotides small insects relative to. The ultra stable cyclotides are promising templates for drug development. Nmr studies of these interactions are described in this article. Cyclotides are macrocyclic knotted peptides originating from plants. Discovery, structure, function, and applications of. For example, engineered cyclotides can have high oral bioavailability that is comparable to small molecule drugs while retaining desired target specificity of the grafted epitopes 6 9.
Stability of cyclotides against heat, chemicals and proteases is due to their unique structure. Discovery, structure, function, and applications of cyclotides. Computational design of hypothetical new peptides based on a cyclotide scaffold as hiv gp120 inhibitor. Design of a cyclotide antagonist of neuropilin1 and 2 that. Design of a mcotibased cyclotide with angiotensin 17. Todays goals become oriented with maestro user interface and some popular tools set up and run a selfdocking job with glide to validate our target model dock a known binder to our target structure learn how to use docking analysis tools empower you to explore additional tools for virtual screening, addressing receptor flexibility, and other tools that will help to. The cyclotide domain may contain either one cyclotide sequence, as in the case of oak1, or multiple copies separated by additional ntr sequences as seen for oak2 and oak4. These applications complement the interest in cyclotides deriving from their unique structures and natural function as host defense molecules. The ones marked may be different from the article in the profile. The full text of this article hosted at is unavailable due to technical difficulties.
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