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Cyclotide Structure-Activity Relationships: Qualitative and Quantitative Approaches Linking Cytotoxic and Anthelmintic Activity to the Clustering of Physicochemical Forces
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
2014 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 3, s. e91430-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cyclotides are a family of plant-derived proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK) motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. Cyclotides exert much of their biological activity via interactions with cell membranes. In this work, we qualitatively and quantitatively analyze the cytotoxic and anthelmintic membrane activities of cyclotides. The qualitative and quantitative models describe the potency of cyclotides using four simple physicochemical terms relevant to membrane contact. Specifically, surface areas of the cyclotides representing lipophilic and hydrogen bond donating properties were quantified and their distribution across the molecular surface was determined. The resulting quantitative structure-activity relation (QSAR) models suggest that the activity of the cyclotides is proportional to their lipophilic and positively charged surface areas, provided that the distribution of these surfaces is asymmetric. In addition, we qualitatively analyzed the physicochemical differences between the various cyclotide subfamilies and their effects on the cyclotides' orientation on the membrane and membrane activity.

Ort, förlag, år, upplaga, sidor
2014. Vol. 9, nr 3, s. e91430-
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-224356DOI: 10.1371/journal.pone.0091430ISI: 000333678100003OAI: oai:DiVA.org:uu-224356DiVA, id: diva2:716847
Tillgänglig från: 2014-05-13 Skapad: 2014-05-09 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Ingår i avhandling
1. Cyclotides evolve: Studies on their natural distribution, structural diversity, and activity
Öppna denna publikation i ny flik eller fönster >>Cyclotides evolve: Studies on their natural distribution, structural diversity, and activity
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The cyclotides are a family of naturally occurring peptides characterized by cyclic cystine knot (CCK) structural motif, which comprises a cyclic head-to-tail backbone featuring six conserved cysteine residues that form three disulfide bonds. This unique structural motif makes cyclotides exceptionally resistant to chemical, thermal and enzymatic degradation. They also exhibit a wide range of biological activities including insecticidal, cytotoxic, anti-HIV and antimicrobial effects.

The cyclotides found in plants exhibit considerable sequence and structural diversity, which can be linked to their evolutionary history and that of their host plants. To clarify the evolutionary link between sequence diversity and the distribution of individual cyclotides across the genus Viola, selected known cyclotides were classified using signature sequences within their precursor proteins. By mapping the classified sequences onto the phylogenetic system of Viola, we traced the flow of cyclotide genes over evolutionary history and were able to estimate the prevalence of cyclotides in this genus. In addition, the structural diversity of the cyclotides was related to specific features of the sequences of their precursor proteins, their evolutionary selection and expression levels.

A number of studies have suggested that the biological activities of the cyclotides are due to their ability to interact with and disrupt biological membranes. To better explain this behavior, quantitative structure-activity relationship (QSAR) models were developed to link the cyclotides’ biological activities to the membrane-interactive physicochemical properties of their molecular surfaces. Both scalar quantities (such as molecular surface areas) and moments (such as the distributions of specific properties over the molecular surface) were systematically taken into account in the development of these models. This approach allows the physicochemical properties of cyclotides to be geometrically interpreted, facilitating the development of guidelines for drug design using cyclotide scaffolds.

Finally, an optimized microwave-assisted Fmoc-SPSS procedure for the total synthesis of cyclotides was developed. Microwave irradiation is used to accelerate and improve all the key steps in cyclotide synthesis, including the assembly of the peptide backbone by Fmoc-SPPS, the cleavage of the protected peptide, and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. 

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 71
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 218
Nyckelord
cyclotide, cyclic cystine knot, evolution, peptide synthesis, chemical ligation, QSAR, Viola, Violaceae, phylogeny
Nationell ämneskategori
Matematik Organisk kemi Fysikalisk kemi Evolutionsbiologi
Forskningsämne
Farmakognosi
Identifikatorer
urn:nbn:se:uu:diva-292668 (URN)978-91-554-9604-3 (ISBN)
Disputation
2016-06-10, B/C4:301, BMC, Husargatan 3, Uppsala, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-05-24 Skapad: 2016-05-06 Senast uppdaterad: 2016-06-15

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