Journal of Peptide Science J. Peptide Sci. 11: 670–676 (2005) Published online 15 August 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/psc.701 Review Small peptides, big world: biotechnological potential in neglected bioactive peptides from arthropod venoms ¶ ADRIANO M. C. PIMENTA* and MARIA ELENA DE LIMA Laborat ´ orio de Venenos e Toxinas Animais, Departamento de Bioqu´ ımica e Imunologia, Instituto de Ciˆ encias Biol ´ ogicas, Universidade Federal de Minas Gerais, Av. Antˆ onio Carlos, 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil Received 03 May 2005; Revised 25 May 2005; Accepted 28 May 2005 Abstract: Until recently, a toxinologist’s tasks involved the search for highly toxic or lethal toxins in animal venoms that could explain the harmful effects in clinically observed symptoms. Most of these toxins were put on evidence using a function to structure approach, in which a biological phenomena observation usually guided the isolation and characterization of the causative molecule. Paving this way, many toxins were promptly purified because of their readily observed effect. Nevertheless, small molecules with micro-effects that are not easily visualized can be relatively neglected or poorly studied. This situation has changed now with the advent of the sensitivity, resolution and accuracy of techniques such as mass spectrometry and proteomic approaches used in toxinology. Taking advantage of these methodologies, small peptides with ‘newly exploited’ biological activities such as vasoactive, hormone-like, antimicrobial and others have been recently given much more attention, enlarging the known repertoire of bioactive molecules found in animal venoms. This article aims to review current knowledge on small biologically active peptides (<3 kDa) found in arthropod venoms and discuss their potentialities as new drug candidates or therapeutic lead compounds. Copyright  2005 European Peptide Society and John Wiley & Sons, Ltd. Keywords: bioactive peptides; arthropod venom; Bradykinin potentiating peptides; antimicrobial peptides; hormone-like peptides INTRODUCTION Animal venoms have been broadly recognized as one of the main sources of biologically active molecules. In fact, animal venoms are a successful evolutionary outcome that has evolved differently along Metazoa Phylum in both predatory and defense senses. To illustrate this extraordinary repertoire, Theakston and Kamiguti [1] have listed more than 2500 animal toxins and other natural products that showed any biological activity. This number tends to increase enormously, since it has been demonstrated that the number of molecules can easily reach 50–300 in each venom, although many of them are still unknown to date [2–9]. Such a richness can be useful to biotechnology in many ways, with the prospection of new drug candi- dates or new chemical entities – that can be used as therapeutic lead compounds – being the most promis- ing. A rough classification of toxins can be made on the basis of their chemical nature (proteins, glycoproteins, peptides, alkaloids, polyamines, biogenic amines and others), their pharmacological or biological effects (neu- rotoxins, myotoxins, vasoactive peptides, hemolytic, * Correspondence to: A. M. C. Pimenta, Laborat ´ orio de Venenos e Toxinas Animais, Depto. de Bioqu´ ımica e Imunologia, ICB, UFMG, Av. Antonio Carlos, 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil; e-mail: apimenta@icb.ufmg.br ¶ Selected paper presented at the 1st International Congress on Natural Peptides to Drugs, 30 November–3 December 2004, Zermatt, Switzerland. cytolytic, necrotic, hemorrhagic, anti-inflammatory, antitumoral, analgesic, antimicrobial and others), their molecular level effects (ionic channel ligands, agonists or antagonists of ionotropic or metabotropic receptors, enzymes, enzymatic inhibitors, others) and, finally, on the basis of their sub-molecular binding sites (such as α- and β -toxins from scorpion venom that bind sites 3 and 4 respectively, from sodium channels). It is interesting to note that among the myriad of molecules that can be found in animal venoms, many of them have their molecular level actions related to receptors and enzymes, which constitute the two main classes of targets for drug action [10]. It is also noteworthy that many of the worldwide top- selling pharmaceutical products are natural products or synthetic and semisynthetic analogs of natural products [11], and yet, proteinaceous molecules and their scaffold templates are poorly exploited. In this review, attention has been paid to small peptides (up to 3 kDa) from arthropod venom sources that act as hormone-like, vasoactive or antimicrobial substances and, for that reason, can be envisaged both as potential drugs and as lead compounds by the pharmaceutical industry. AN OVERVIEW ON NEGLECTED PEPTIDES Small peptides such as hormones, neuropeptides, cytokines and enzyme inhibitors play a key role in many Copyright  2005 European Peptide Society and John Wiley & Sons, Ltd.