High Proteolytic Resistance of Spider-Derived Inhibitor Cystine Knots

Kikuchi, Keiko; Sugiura, Mika; Kimura, Tadashi

doi:10.1155/2015/537508

Cited by 27 publications

(22 citation statements)

References 48 publications

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“…It is often claimed that ICK peptides are highly stable and resistant to thermal, chemical and enzymatic degradation and this has been demonstrated for several spider venom peptides, ω-Hv1a, ProTx-II, GsMTx-4, and GTx1-15 (Herzig and King, 2015;Kikuchi et al, 2015).…”

Section: Stability Of Hm3a and Pctx1mentioning

confidence: 98%

Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1

Cristofori-Armstrong

Escoubas³

et al. 2017

Neuropharmacology

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Please cite this article as: Er, S.Y., Cristofori-Armstrong, B., Escoubas, P., Rash, L.D., Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1, Neuropharmacology (2017), doi: 10.1016/j.neuropharm.2017.03.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. interaction and contribute to the subtype-dependent effects of the peptide. Despite its high sequence similarity with PcTx1, Hm3a showed higher levels of stability over 48 hours.Overall, Hm3a represents a potent, highly stable tool for the study of ASICs and will be particularly useful when stability in biological fluids is required, for example in long term in vitro cell-based assays and in vivo experiments.

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Section: Stability Of Hm3a and Pctx1mentioning

confidence: 98%

Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1

Cristofori-Armstrong

Escoubas³

et al. 2017

Neuropharmacology

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“…). Although not a true knot in a mathematical sense, since it can be untied by a non‐bond‐breaking geometrical transformation, the cystine knot nevertheless provides knottin peptides with exceptional chemical and thermal stability, as well as resistance to proteases . Remarkably, some spider‐venom knottins are stable for more than a week in insect hemolymph and have melting temperatures higher than 80 °C …”

Section: Knotted Spider‐venom Peptides: Potent Stable and Orally Acmentioning

confidence: 99%

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

King

2019

Pest Management Science

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Spider venoms are complex chemical arsenals that contain a rich variety of insecticidal toxins. However, the major toxin class in many spider venoms is disulfide‐rich peptides known as knottins. The knotted three‐dimensional fold of these mini‐proteins provides them with exceptional chemical and thermal stability as well as resistance to proteases. In contrast with other bioinsecticides, which are often slow‐acting, spider knottins are fast‐acting neurotoxins. In addition to being potently insecticidal, some knottins have exceptional taxonomic selectivity, being lethal to key agricultural pests but innocuous to vertebrates and beneficial insects such as bees. The intrinsic oral activity of these peptides, combined with the ability of aerosolized knottins to penetrate insect spiracles, has enabled them to be developed commercially as eco‐friendly bioinsecticides. Moreover, it has been demonstrated that spider‐knottin transgenes can be used to engineer faster‐acting entomopathogens and insect‐resistant crops. © 2019 Society of Chemical Industry

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“…As an example, the spider toxin ProTx-I is degraded rapidly by trypsin, while the closely related ProTx-II from the same organism (<1.5 Å C α rmsd) [9] is completely stable under the same conditions. [10] The need for improved properties in some disulfide-rich systems has motivated chemists to develop and apply various chemical alterations; [11] examples include backbone cyclization or replacement of the disulfides with other moieties. [12] A key challenge in such work is maintaining the precise 3-dimensional fold of a prototype after chemical modification.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous‐Backbone Foldamer Mimics of a Computationally Designed, Disulfide‐Rich Miniprotein

2018

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Disulfide-rich peptides have found widespread use in the development of bioactive agents; however, low proteolytic stability and difficulty exerting synthetic control over chain topology present barriers to applications in some systems. Here, we report a method that enables creation of artificial backbone (“foldamer”) mimics of compact, disulfide-rich tertiary folds. Systematic replacement of a subset of natural α-residues with various artificial building blocks in the context of a computationally designed prototype sequence leads to “heterogeneous-backbone” variants that undergo clean oxidative folding, adopt tertiary structures indistinguishable from the prototype, and enjoy proteolytic protection beyond that inherent to the topologically constrained scaffold. Collectively, these results demonstrate systematic backbone substitution as a viable method to engineer the properties of disulfide-rich sequences and expands the repertoire of protein mimicry by foldamers to an exciting new structural class.

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High Proteolytic Resistance of Spider-Derived Inhibitor Cystine Knots

Cited by 27 publications

References 48 publications

Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1

Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

Heterogeneous‐Backbone Foldamer Mimics of a Computationally Designed, Disulfide‐Rich Miniprotein

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