Dataset Information

High Proteolytic Resistance of Spider-Derived Inhibitor Cystine Knots.

ABSTRACT: Proteolytic stability in gastrointestinal tract and blood plasma is the major obstacle for oral peptide drug development. Inhibitor cystine knots (ICKs) are linear cystine knot peptides which have multifunctional properties and could become promising drug scaffolds. ProTx-I, ProTx-II, GTx1-15, and GsMTx-4 were spider-derived ICKs and incubated with pepsin, trypsin, chymotrypsin, and elastase in physiological conditions to find that all tested peptides were resistant to pepsin, and ProTx-II, GsMTx-4, and GTx1-15 showed resistance to all tested proteases. Also, no ProTx-II degradation was observed in rat blood plasma for 24 hours in vitro and ProTx-II concentration in circulation decreased to half in 40?min, indicating absolute stability in plasma and fast clearance from the system. So far, linear peptides are generally thought to be unsuitable in vivo, but all tested ICKs were not degraded by pepsin and stomach could be selected for the alternative site of drug absorption for fast onset of the drug action. Since spider ICKs are selective inhibitors of various ion channels which are related to the pathology of many diseases, engineered ICKs will make a novel class of peptide medicines which can treat variety of bothering symptoms.

SUBMITTER: Kikuchi K

PROVIDER: S-EPMC4710912 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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High Proteolytic Resistance of Spider-Derived Inhibitor Cystine Knots.

Kikuchi Kyoko K Sugiura Mika M Kimura Tadashi T

International journal of peptides 20151230

Proteolytic stability in gastrointestinal tract and blood plasma is the major obstacle for oral peptide drug development. Inhibitor cystine knots (ICKs) are linear cystine knot peptides which have multifunctional properties and could become promising drug scaffolds. ProTx-I, ProTx-II, GTx1-15, and GsMTx-4 were spider-derived ICKs and incubated with pepsin, trypsin, chymotrypsin, and elastase in physiological conditions to find that all tested peptides were resistant to pepsin, and ProTx-II, GsMT ...[more]

PMID: 26843868

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Project description:BACKGROUND: Knottins are small, diverse and stable proteins with important drug design potential. They can be classified in 30 families which cover a wide range of sequences (1621 sequenced), three-dimensional structures (155 solved) and functions (> 10). Inter knottin similarity lies mainly between 15% and 40% sequence identity and 1.5 to 4.5 Å backbone deviations although they all share a tightly knotted disulfide core. This important variability is likely to arise from the highly diverse loops which connect the successive knotted cysteines. The prediction of structural models for all knottin sequences would open new directions for the analysis of interaction sites and to provide a better understanding of the structural and functional organization of proteins sharing this scaffold. RESULTS: We have designed an automated modeling procedure for predicting the three-dimensionnal structure of knottins. The different steps of the homology modeling pipeline were carefully optimized relatively to a test set of knottins with known structures: template selection and alignment, extraction of structural constraints and model building, model evaluation and refinement. After optimization, the accuracy of predicted models was shown to lie between 1.50 and 1.96 Å from native structures at 50% and 10% maximum sequence identity levels, respectively. These average model deviations represent an improvement varying between 0.74 and 1.17 Å over a basic homology modeling derived from a unique template. A database of 1621 structural models for all known knottin sequences was generated and is freely accessible from our web server at http://knottin.cbs.cnrs.fr. Models can also be interactively constructed from any knottin sequence using the structure prediction module Knoter1D3D available from our protein analysis toolkit PAT at http://pat.cbs.cnrs.fr. CONCLUSIONS: This work explores different directions for a systematic homology modeling of a diverse family of protein sequences. In particular, we have shown that the accuracy of the models constructed at a low level of sequence identity can be improved by 1) a careful optimization of the modeling procedure, 2) the combination of multiple structural templates and 3) the use of conserved structural features as modeling restraints.

Dataset Information

High Proteolytic Resistance of Spider-Derived Inhibitor Cystine Knots.

Publications

High Proteolytic Resistance of Spider-Derived Inhibitor Cystine Knots.

Similar Datasets

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