Molecular Grafting onto a Stable Framework Yields Novel Cyclic Peptides for the Treatment of Multiple Sclerosis

Wang, Conan K.; Gruber, Christian W.; Cemazar, Masa; Siatskas, Christopher; Tagore, P.; Payne, Natalie Lisa; Sun, Guizhi; Wang, Shunhe; Bernard, Claude Charles Andre; Craik, David J.

doi:10.1021/cb400548s

Cited by 138 publications

(134 citation statements)

References 38 publications

(74 reference statements)

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“…The gastrointestinal uptake and systemic biodistribution of a derivatized cyclotide ([T20K-VivoTag]kB1) has been confirmed by IVIS. Although the VivoTag-labeled cyclotide may exhibit different physicochemical properties, IVIS seemed to be a valid model system to monitor the trajectory of the cyclotide following oral administration based on the known stability of cyclotides in proteolytic environment and at acidic conditions (32).…”

Section: Discussionmentioning

confidence: 99%

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

Thell

Hellinger

Sahin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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118

141

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Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. It is characterized by autoreactive T cells that induce demyelination and neuronal degradation. Treatment options are still limited and several MS medications need to be administered by parenteral application but are modestly effective. Oral active drugs such as fingolimod have been weighed down by safety concerns. Consequently, there is a demand for novel, especially orally active therapeutics. Nature offers an abundance of compounds for drug discovery. Recently, the circular plant peptide kalata B1 was shown to silence T-cell proliferation in vitro in an IL-2-dependent mechanism. Owing to this promising effect, we aimed to determine in vivo activity of the cyclotide [T20K]kalata B1 using the MS mouse model experimental autoimmune encephalomyelitis (EAE). Treatment of mice with the cyclotide resulted in a significant delay and diminished symptoms of EAE by oral administration. Cyclotide application substantially impeded disease progression and did not exhibit adverse effects. Inhibition of lymphocyte proliferation and the reduction of proinflammatory cytokines, in particular IL-2, distinguish the cyclotide from other marketed drugs. Considering their stable structural topology and oral activity, cyclotides are candidates as peptide therapeutics for pharmaceutical drug development for treatment of T-cell-mediated disorders.cyclic peptides | multiple sclerosis | immunopharmacology | plant natural product | drug discovery

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Section: Discussionmentioning

confidence: 99%

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

Thell

Hellinger

Sahin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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118

141

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“…The goal to implement molecular grafting was to design molecules that retain both, the activity of an MS-related antigen [myelin oligodendrocyte glycoprotein (MOG)] and the structure and stability of the scaffold onto which the epitope is grafted (Wang et al 2014). …”

Section: Cyclotides and Their Immunomodulatory Propertiesmentioning

confidence: 99%

T20K: An Immunomodulatory Cyclotide on Its Way to the Clinic

Gründemann

Stenberg²,

Gruber

2018

Int J Pept Res Ther

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Cyclotides represent a new class of natural plant compounds, which could be considered ideal "template" molecules for drug design. Their structure is characterized by a circular cystine-knot motif, comprising an amino acid chain stabilized by three conserved disulfide bonds in a knotted arrangement, and a head-to-tail cyclized peptide backbone. Our laboratories initially demonstrated their activity to modulate immune cell signaling. Following nearly a decade of extensive research, we are now aware that cyclotide-based peptides provide an outstanding opportunity to develop novel drugs for autoimmune disorders, especially multiple sclerosis. Here we review and demonstrate the potential of cyclotide-derived peptide therapeutics on their way from preclinical studies to clinical trials as promising therapeutics in immunopharmacological applications.

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“…[86] The potential of grafted cyclotides in the context of multiple sclerosis has been also explored by grafting peptide sequences from the MOG35-55 epitope onto the cyclotide kalata B1. [87] …”

Section: Engineered Cyclotides With Novel Biological Activiesmentioning

confidence: 99%

Cyclotides: Overview and Biotechnological Applications

Gould

Camarero

2017

ChemBioChem

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Cyclotides are globular microproteins with a unique head-to-tail cyclized backbone, stabilized by three disulfide bonds forming a cystine knot. This unique circular backbone topology and knotted arrangement of three disulfide bonds makes them exceptionally stable to chemical, thermal and biological degradation compared to other peptides of similar size. In addition, cyclotides have been shown to be highly tolerant to sequence variability aside from the conserved residues forming the cystine knot. Cyclotides can also cross cellular membranes and are able to modulate intracellular protein-protein interactions both in vitro and in vivo. All these features make cyclotides appear as highly promising leads or frameworks for the design of peptide-based diagnostic and therapeutic tools. This article provides an overview on cyclotides and their applications as molecular imaging agents and peptide-based therapeutics.

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Molecular Grafting onto a Stable Framework Yields Novel Cyclic Peptides for the Treatment of Multiple Sclerosis

Cited by 138 publications

References 38 publications

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

T20K: An Immunomodulatory Cyclotide on Its Way to the Clinic

Cyclotides: Overview and Biotechnological Applications

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