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      From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery

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          Abstract

          Animal poisons and venoms are comprised of different classes of molecules displaying wide-ranging pharmacological activities. This review aims to provide an in-depth view of toxin-based compounds from terrestrial and marine organisms used as diagnostic tools, experimental molecules to validate postulated therapeutic targets, drug libraries, prototypes for the design of drugs, cosmeceuticals, and therapeutic agents. However, making these molecules applicable requires extensive preclinical trials, with some applications also demanding clinical trials, in order to validate their molecular target, mechanism of action, effective dose, potential adverse effects, as well as other fundamental parameters. Here we go through the pitfalls for a toxin-based potential therapeutic drug to become eligible for clinical trials and marketing. The manuscript also presents an overview of the current picture for several molecules from different animal venoms and poisons (such as those from amphibians, cone snails, hymenopterans, scorpions, sea anemones, snakes, spiders, tetraodontiformes, bats, and shrews) that have been used in clinical trials. Advances and perspectives on the therapeutic potential of molecules from other underexploited animals, such as caterpillars and ticks, are also reported. The challenges faced during the lengthy and costly preclinical and clinical studies and how to overcome these hindrances are also discussed for that drug candidates going to the bedside. It covers most of the drugs developed using toxins, the molecules that have failed and those that are currently in clinical trials. The article presents a detailed overview of toxins that have been used as therapeutic agents, including their discovery, formulation, dosage, indications, main adverse effects, and pregnancy and breastfeeding prescription warnings. Toxins in diagnosis, as well as cosmeceuticals and atypical therapies (bee venom and leech therapies) are also reported. The level of cumulative and detailed information provided in this review may help pharmacists, physicians, biotechnologists, pharmacologists, and scientists interested in toxinology, drug discovery, and development of toxin-based products.

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          Most cited references259

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          Venoms as a platform for human drugs: translating toxins into therapeutics.

          Glenn King (2011)
          An extraordinarily diverse range of animals have evolved venoms for predation, defence, or competitor deterrence. The major components of most venoms are peptides and proteins that are often protease-resistant due to their disulfide-rich architectures. Some of these toxins have become valuable as pharmacological tools and/or therapeutics due to their extremely high specificity and potency for particular molecular targets. There are currently six FDA-approved drugs derived from venom peptides or proteins. This article surveys the current pipeline of venom-derived therapeutics and critically examines the potential of peptide and protein drugs derived from venoms. Emerging trends are identified, including an increasing industry focus on disulfide-rich venom peptides and the use of a broader array of molecular targets in order to develop venom-based therapeutics for treating a wider range of clinical conditions. Key technical advances in combination with a renewed industry-wide focus on biologics have converged to provide a larger than ever pipeline of venom-derived therapeutics. Disulfide-rich venom peptides obviate some of the traditional disadvantages of therapeutic peptides and some may be suitable for oral administration. Moreover, some venom peptides can breach the blood brain barrier and translocate across cell membranes, which opens up the possibility of exploiting molecular targets not previously accessible to peptide drugs.
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            Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas.

            The recent identification in Heloderma horridum venom of exendin-3, a new member of the glucagon superfamily that acts as a pancreatic secretagogue, prompted a search for a similar peptide in Heloderma suspectum venom. An amino acid sequencing assay for peptides containing an amino-terminal histidine residue (His1) was used to isolate a 39-amino acid peptide, exendin-4, from H. suspectum venom. Exendin-4 differs from exendin-3 by two amino acid substitutions, Gly2-Glu3 in place of Ser2-Asp3, but is otherwise identical. The structural differences make exendin-4 distinct from exendin-3 in its bioactivity. In dispersed acini from guinea pig pancreas, natural and synthetic exendin-4 stimulate a monophasic increase in cAMP beginning at 100 pM that plateaus at 10 nM. The exendin-4-induced increase in cAMP is inhibited progressively by increasing concentrations of the exendin receptor antagonist, exendin-(9-39) amide. Unlike exendin-3, exendin-4 does not stimulate a second rise in acinar cAMP at concentrations greater than 100 nM, does not stimulate amylase release, and does not inhibit the binding of radiolabeled vasoactive intestinal peptide to acini. This indicates that in dispersed pancreatic acini, exendin-4 interacts only with the recently described exendin receptor.
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              Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci.

              Toward the goal of developing an optical imaging contrast agent that will enable surgeons to intraoperatively distinguish cancer foci from adjacent normal tissue, we developed a chlorotoxin:Cy5.5 (CTX:Cy5.5) bioconjugate that emits near-IR fluorescent signal. The probe delineates malignant glioma, medulloblastoma, prostate cancer, intestinal cancer, and sarcoma from adjacent non-neoplastic tissue in mouse models. Metastatic cancer foci as small as a few hundred cells were detected in lymph channels. Specific binding to cancer cells is facilitated by matrix metalloproteinase-2 (MMP-2) as evidenced by reduction of CTX:Cy5.5 binding in vitro and in vivo by a pharmacologic blocker of MMP-2 and induction of CTX:Cy5.5 binding in MCF-7 cells following transfection with a plasmid encoding MMP-2. Mouse studies revealed that CTX:Cy5.5 has favorable biodistribution and toxicity profiles. These studies show that CTX:Cy5.5 has the potential to fundamentally improve intraoperative detection and resection of malignancies.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/423555
                URI : https://loop.frontiersin.org/people/430512
                URI : https://loop.frontiersin.org/people/1035928
                URI : https://loop.frontiersin.org/people/953307
                URI : https://loop.frontiersin.org/people/764581
                URI : https://loop.frontiersin.org/people/1022421
                URI : https://loop.frontiersin.org/people/1003619
                URI : https://loop.frontiersin.org/people/866955
                URI : https://loop.frontiersin.org/people/1036170
                URI : https://loop.frontiersin.org/people/1003651
                URI : https://loop.frontiersin.org/people/1037030
                URI : https://loop.frontiersin.org/people/765310
                URI : https://loop.frontiersin.org/people/1036187
                URI : https://loop.frontiersin.org/people/41350
                URI : https://loop.frontiersin.org/people/1035934
                URI : https://loop.frontiersin.org/people/423558
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                24 July 2020
                2020
                : 11
                : 1132
                Affiliations
                [1] 1 Laboratory of Animal Toxins, Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo , Ribeirão Preto, Brazil
                [2] 2 Health and Science Institute, Paulista University , São José do Rio Pardo, Brazil
                [3] 3 Postgraduate Program in Pharmaceutical Sciences, Vila Velha University , Vila Velha, Brazil
                [4] 4 Department of Pharmacy, Federal Institute of Education, Science and Technology of Paraná , Palmas, Brazil
                [5] 5 Postgraduate Program in Ecosystem Ecology, Vila Velha University , Vila Velha, Brazil
                [6] 6 Medical School, Federal University of Roraima , Boa Vista, Brazil
                Author notes

                Edited by: Yuri N. Utkin, Institute of Bioorganic Chemistry (RAS), Russia

                Reviewed by: Sakthivel Vaiyapuri, University of Reading, United Kingdom; Helena Safavi, The University of Utah, United States; Zhonghua Liu, Hunan Normal University, China

                *Correspondence: Karla de Castro Figueiredo Bordon, karla@ 123456fcfrp.usp.br ; Eliane Candiani Arantes, ecabraga@ 123456fcfrp.usp.br

                This article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2020.01132
                7396678
                32848750
                fb3d618e-b549-479e-9977-92d1eb34ee59
                Copyright © 2020 Bordon, Cologna, Fornari-Baldo, Pinheiro-Júnior, Cerni, Amorim, Anjolette, Cordeiro, Wiezel, Cardoso, Ferreira, Oliveira, Boldrini-França, Pucca, Baldo and Arantes

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 April 2020
                : 13 July 2020
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 307, Pages: 29, Words: 15457
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo 10.13039/501100001807
                Award ID: 2019/10173-6
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                poison,venom,toxin,drug discovery,scorpion,snake,toad,conus
                Pharmacology & Pharmaceutical medicine
                poison, venom, toxin, drug discovery, scorpion, snake, toad, conus

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