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Like most natural product libraries animal venoms have long been recognized as potentially rich source of biologically active molecules with the potential to be mined for the discovery of drugs, drug leads and/or biosimilars. In this work we demonstrate as a proof of concept a novel approach to explore venoms for potential biosimilarity to other drugs based on their ability to alter the transcriptomes of test cell lines followed by informatic searches and Connectivity Mapping to match the action of the venom on the cell gene expression to that of other drugs in the Connectivity Map (C-Map) database. As our test animal venom we chose Heloderma suspectum venom (Gila monster) since exendin-4, a glucagon-like peptide 1 receptor agonist, isolated from the venom is currently on the market to treat type 2 diabetes. The action of Byetta(®) (exentide, synthetic exendin-4), was also used in transcriptome studies. Analysis of transcriptomes from cells treated with the venom or the drug showed similarities as well as differences. The former case was primarily attributed to the fact that Gila monster venom likely contains a variety of biologically active molecules that could alter the MCF7 cell transcriptome compared to that of the single perturbant Byetta(®). Using Ingenuity Pathway Analysis software, insulin-like growth factor 1 signaling was identified in the category of "Top Canonical Pathways" for both the venom and Byetta(®). In the category of "Top Molecules" up-regulated, both venom and Byetta(®) shared IL-8, cyclic AMP-dependent transcription factor 3 (ATF-3), neuron-derived orphan receptor 1 (NR4A3), dexamethasone-induced Ras-related protein 1 (RASD1) and early growth response protein 1, (EGR-1) all with potential relevance in diabetes. Using Connectivity Mapping, Gila monster venom showed positive correlation with 1732 instances and negative correlation with 793 instances in the Connectivity database whereas Byetta(®) showed positive correlation with 1692 instances and negative correlation with 868 instances. Interestingly, the Gila monster venom and Byetta(®) both showed positive correlation with the anti-diabetic drugs troglitazone, of the thiazolidinedione class, and metformin, of the biguanide class, although Byetta(®) as a glucagon-like peptide-1 (GLP-1) agonist functions in a different manner than either of these two classes of anti-diabetic drugs. In summary, despite the fact that Gila monster venom contains a mixture of biologically active molecules, similarities in terms of perturbation of gene expression profiles on MCF7 cells were observed between the venom and the drug Byetta(®). Furthermore, using Connectivity Mapping the Gila monster venom was demonstrated to have nodes of positive correlation to several anti-diabetic drugs two of which were the same as observed with Byetta(®). Therefore, this study suggests that by using this approach novel drug activities heretofore unconsidered may be discovered in venoms using informatic tools and Connectivity Mapping., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Animal venomous secretions have been explored as source of active substances affecting mammal hemostasis. These active principles impinge on key elements of almost all physiologic pathways and have an enormous potential in the development of new therapeutic drugs. The envenomation caused by the caterpillar Lonomia obliqua (lonomism) is characterized by a hemorrhagic clinical profile. Investigations of caterpillar venom have, in general, involved the isolation and biochemical characterization of active principles related to the pathophysiology of envenomation. In the last few years, these studies focused on the caterpillar's secretions pro-coagulant, fibrin(ogen)olytic, hemolytic, edematogenic and nociceptive activities. Recently, a significant advance was achieved as a result of a transcriptome study, which generated a catalog of putative toxic proteins in the caterpillar venom, giving rise to hypotheses on the molecular basis of pathogenesis which could be experimentally explored. In this investigation, using a microarray methodology, we analyzed the effects of the caterpillar venom on the gene expression profile of cultured human fibroblasts with the aim of gaining insight into genes possibly associated with the clinical manifestations of lonomism. Our hypothesis was that both the direct action L. obliqua venomous proteins on the host as well as an indirect effect caused by alteration in the gene expression pattern in host tissues could function in concert and perhaps synergistically to give rise to the profound symptoms observed during lonomism. Interesting changes in the expression pattern of some genes, such as IL-8, prostaglandin-endoperoxide synthase 2, urokinase-type plasminogen activator receptor and tissue factor, were observed in treated fibroblasts, which could contribute to some of the observed pathological sequela in lonomism. Thus, lonomism appears to be a result of both the previously described direct effects of the venom as well as indirect effects caused by changes in host gene expression profiles. These studies have enhanced our understanding of lonomism and may contribute to insights into more effective treatments.