Peptide Chemical Biology
Our research is conducted at the interface between chemistry and biology. Our ultimate aim is to understand and explore the chemistry of nature and and natural processes that can be useful for drug discovery. In particular we explore the fundamentals of peptides with possible pharmaceutical and medical applications.
Peptides and proteins are produced in all living organisms to fulfill important biological functions. Hence one would think that they would constitute one of the most common types of drug substances. However, the use of peptides and proteins is hampered becasue of their lack of stability.
We have found that some plants produce a cocktail of very unusual polypeptides that are head-to-tail-cyclized via amide bonds. These cyclic polypeptides, known as cyclotides (cyclo-peptides), are around 30 amino acid residues long and show an exceptional chemical and biological stability. This is partly explained by their cyclic backbone, but in addition they contain six conserved cysteine residues that are involved in three disulfide bonds. Together these features confine the so called cyclic cystine knot motif (CCK), as shown in the figure below.
The central core of the cyclotides consists of three disulfides, marked in yellow and represented in "stick and ball" mode in the figure below. The disulfide bonds to the left and to the right and their connecting backbone (marked in grey) form a ring through which the third disulfide bond is threaded. This is the cystine knot, which together with the cyclic backbone defines the cyclic cystine knot motif.
The cyclic cystine knot makes cyclotides highly suitable for protein engineering applications.
Biologically active peptide sequences can be succesfully be inserted into the stable cyclotide scaffold. Native cyclotides also show a variety of biological activities, such as contraction of the uterus (which was why the first cyclotide kalata B1 was discovered), and anti-HIV and insecticidal activity.
We have recently shown that they also have potent cytotoxic and antibacterial effects, which is currently followed up by structure activity studies and studies of cyclotides effect on artifical cell membranes in the form of liposomes.
For more information, including the possibilities to do student projects in our group, please follow the links to the left or contact Ulf Göransson. You can also find more information about cyclotides in particular in Cybase, a database dedicated to cyclic proteins, and cystine knotted peptides in general in The Knottin database.
Our research is supported by the Swedish Research Council Vetenskapsrådet, and the Swedish Research Council FORMAS.
Advances in Botanical Research, volyme 76, is dedicated to cyclotide research. We contributed with Chapter 2: Cyclotides in Violaceae.
In the article "A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity", we describe the discovery, sequencing, chemical synthesis, structure determination and bioactivity of this novel peptide.
Cover Journal of Natural Products!
From Jan to June 2014 our research is highlighted on the cover of JNP! This will be followed up by a revie
- Cyclotide Evolution: Insights from the Analyses of Their Precursor Sequences, Structures and Distribution in Violets (Viola). 2017
- Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins. 2017
- Spasmolytic Mechanism of Aqueous Licorice Extract on Oxytocin-Induced Uterine Contraction through Inhibiting the Phosphorylation of Heat Shock Protein 27. 2017
- Essential oils of aromatic Egyptian plants repel nymphs of the tick Ixodes ricinus (Acari: Ixodidae). 2017
- Bactericidal activity of cyclotides where phosphatidylethanolamine-lipid selectivity determines antimicrobial spectra. 2017
- Single-step purification of cyclotides using affinity chromatography. 2017
- Cytotoxic Effects of Sarcophyton sp Soft Corals-Is There a Correlation to Their NMR Fingerprints?. 2017
- Phytochemical Profiles and Antimicrobial Activities of Allium cepa Red cv. and A. sativum Subjected to Different Drying Methods: A Comparative MS-Based Metabolomics. 2017
- Resistance to the Cyclotide Cycloviolacin O2 in Salmonella enterica Caused by Different Mutations That Often Confer Cross-Resistance or Collateral Sensitivity to Other Antimicrobial Peptides. 2017
- Engineering Of A Minimalized Domain Derived From Human Host Defense Peptide LL-37 Into A Stable And Potent Antimicrobial Drug Lead. 2016
Are you a student at the Faculty of Pharmacy, do not forget that you can apply to the Summer research school, SOFOSKO!