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Toxins 2017, 9(11), 350; https://doi.org/10.3390/toxins9110350

Overlooked Short Toxin-Like Proteins: A Shortcut to Drug Design

1
Department of Biological Chemistry, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
2
Institute for Computational Health Sciences, UCSF, San Francisco, CA 94158, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Steve Peigneur
Received: 19 September 2017 / Revised: 22 October 2017 / Accepted: 25 October 2017 / Published: 29 October 2017
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
View Full-Text   |   Download PDF [3056 KB, uploaded 30 October 2017]   |  

Abstract

Short stable peptides have huge potential for novel therapies and biosimilars. Cysteine-rich short proteins are characterized by multiple disulfide bridges in a compact structure. Many of these metazoan proteins are processed, folded, and secreted as soluble stable folds. These properties are shared by both marine and terrestrial animal toxins. These stable short proteins are promising sources for new drug development. We developed ClanTox (classifier of animal toxins) to identify toxin-like proteins (TOLIPs) using machine learning models trained on a large-scale proteomic database. Insects proteomes provide a rich source for protein innovations. Therefore, we seek overlooked toxin-like proteins from insects (coined iTOLIPs). Out of 4180 short (<75 amino acids) secreted proteins, 379 were predicted as iTOLIPs with high confidence, with as many as 30% of the genes marked as uncharacterized. Based on bioinformatics, structure modeling, and data-mining methods, we found that the most significant group of predicted iTOLIPs carry antimicrobial activity. Among the top predicted sequences were 120 termicin genes from termites with antifungal properties. Structural variations of insect antimicrobial peptides illustrate the similarity to a short version of the defensin fold with antifungal specificity. We also identified 9 proteins that strongly resemble ion channel inhibitors from scorpion and conus toxins. Furthermore, we assigned functional fold to numerous uncharacterized iTOLIPs. We conclude that a systematic approach for finding iTOLIPs provides a rich source of peptides for drug design and innovative therapeutic discoveries. View Full-Text
Keywords: neurotoxin; protein families; disulfide bonds; antimicrobial peptide; ion channel inhibitor; ClanTox; complete proteome; comparative proteomics; machine learning; insects neurotoxin; protein families; disulfide bonds; antimicrobial peptide; ion channel inhibitor; ClanTox; complete proteome; comparative proteomics; machine learning; insects
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Linial, M.; Rappoport, N.; Ofer, D. Overlooked Short Toxin-Like Proteins: A Shortcut to Drug Design. Toxins 2017, 9, 350.

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