Immunosuppressive peptides and their therapeutic applications

Thell, Kathrin; Hellinger, Roland; Schabbauer, Gernot; Gruber, Christian W.

doi:10.1016/j.drudis.2013.12.002

Cited by 83 publications

(80 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Incidentally, cyclosporine A produced by the fungus Tolypocladium inflatum is also a cyclic (undeca)peptide and it is considered the prototype of a new generation of immunosuppressive drugs (42). Historically, cyclosporine A was instrumental to the development of modern immunopharmacology and it is still in clinical use today (29,36). Despite the limitations of such comparisons, we believe that the rich diversity of cyclotides (17,43) justifies their position as a treasure trove for drug discovery.…”

Section: Discussionmentioning

confidence: 99%

“…In a head-to-head comparison of [T20K]kB1 and fingolimod, a recently approved orally bioavailable drug to prevent MS progression, the cyclotide seemed to be an advantageous therapeutic option when administered at a single dose; fingolimod was only effective with multiple administrations, and best at daily administration of its therapeutic dose. Consequently, cyclotides exhibiting oral activity are very promising acquisitions in drug discovery, not only regarding the treatment of MS but as a potential option for oral treatment of other autoimmune-related diseases (25,36). Successful advances in chemical and recombinant synthesis (37,38) as well as enzymatic folding (39) and cyclization (40) may yield affordable production of cyclotides at clinical scale in the near future.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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.

Self Cite

118

141

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 99%

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.

Self Cite

118

141

View full text Add to dashboard Cite

show abstract

“…[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

View full text Add to dashboard Cite

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.

show abstract

“…We demonstrated that cyclotides, in particular T20K, inhibit T-cell proliferation by downregulation of IL-2 release as well as IL-2R/CD25 surface expression and effector activity performance (Gründemann et al 2013;Thell et al 2014). The cytokine IL-2 physiologically plays an important role in T-lymphocyte activation and acts as autocrine factor to stimulate T-cell proliferation (Malek and Bayer 2004).…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Immunosuppressive peptides and their therapeutic applications

Cited by 83 publications

References 89 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

Cyclotides: Overview and Biotechnological Applications

T20K: An Immunomodulatory Cyclotide on Its Way to the Clinic

Contact Info

Product

Resources

About