Current Pharmaceutical Biotechnology, 2020, 21, 97-109

97 Send Orders for Reprints to [email protected] Current Pharmaceutical Biotechnology, 2020, 21, 97-109 REVIEW ARTICLE ISSN: 1389-2010 eISSN: 1873-4316 Current Pharmaceutical Nanoparticles Functionalized with Venom-Derived Peptides and Toxins Biotechnology Impact Factor: 1.516 The international for Pharmaceutical Applications journal for timely in-depth reviews in Pharmaceutical Biotechnology BENTHAM SCIENCE Ana P. dos Santos1, Tamara G. de Araújo2 and Gandhi Rádis-Baptista3,* 1Program of Post-graduation in Pharmaceutical Sciences (FFEO/UFC), Federal University of Ceara, Ceara, Brazil; 2Department of Pharmacy, Federal University of Ceara, Ceara, Brazil; 3Institute of Marine Sciences, Federal Universi- ty of Ceara, Ceara, Brazil Abstract: Venom-derived peptides display diverse biological and pharmacological activities, making them useful in drug discovery platforms and for a wide range of applications in medicine and pharmaceutical biotechnology. Due to their target specificities, venom peptides have the potential to be developed into biopharmaceuticals to treat various health conditions such as diabetes mellitus, hypertension, and chronic pain. Despite the high potential for drug development, several limitations preclude the di- A R T I C L E H I S T O R Y rect use of peptides as therapeutics and hamper the process of converting venom peptides into pharmaceuticals. These limitations include, for instance, chemical instability, poor oral absorption, short half- life, and off-target cytotoxicity. One strategy to overcome these disadvantages relies on the formula- Received: January 25, 2019 Revised: April 17, 2019 tion of bioactive peptides with nanocarriers. A range of biocompatible materials are now available that Accepted: May 08, 2019 can serve as nanocarriers and can improve the bioavailability of therapeutic and venom-derived peptides for clinical and diagnostic application. Examples of isolated venom peptides and crude animal DOI: 10.2174/1389201020666190621104624 venoms that have been encapsulated and formulated with different types of nanomaterials with promising results are increasingly reported. Based on the current data, a wealth of information can be collect- ed regarding the utilization of nanocarriers to encapsulate venom peptides and render them bioavaila- ble for pharmaceutical use. Overall, nanomaterials arise as essential components in the preparation of biopharmaceuticals that are based on biological and pharmacological active venom-derived peptides. Keywords: Venom-derived peptides, therapeutic peptides, biopharmaceuticals, nanotechnology, drug delivery system, toxins. 1. INTRODUCTION cone snails, sea anemones, jellyfish, fish, cephalopods, echi- noderms, several insect orders (such as ants, bees, wasps), Venomous animals are specialized predators that have and even some mammals (the platypus, shrews, vampire developed over millions of years of evolution, the ability to bats) [3]. Venoms are delivered to prey or predators through produce venoms, and secretions composed of an incredible diverse types of specialized structures such as barbs, beaks, structural and functional diversity of toxins for their biologi- fangs, or modified teeth, harpoons, nematocysts, pinchers, cal purposes [1]. These compounds have evolved to deter, proboscises, spines, sprays, spurs, and stingers [4]. Some of immobilize or kill a range of prey, predators, or competitors, these animals can produce venoms in special glands, while in which the toxins can affect essential and vulnerable physi- others may contain toxic substances that spread throughout ological processes of the affected organism, such as neuro- their body tissues [5]. muscular signaling, hemostasis, and cardiovascular function, among others [2]. When injected into animals or human vic- Over time, the biological diversity and potency of ven- tims, usually in small amounts, these compounds can cause oms have become more refined, so that they display high harmful disorders and even death. Venoms are composed of specificity to their pharmacologically active targets, render- complex mixtures of salts, low molecular weight organic ing animal toxin compounds extremely valuable for the de- molecules such as polyamines, amino acids, venom en- velopment of new therapeutics and adjuvant strategies in zymes, and, importantly, pharmacologically active peptides clinics [6, 7]. Venom-derived peptides act with excellent and polypeptides. A wide diversity of animals has developed selectivity and potency on several biological targets, includ- the ability to produce these cocktails of compounds, such as ing ligand- and voltage-dependent ion channels, G-protein snakes, lizards, scorpions, spiders, centipedes, ticks, leeches, coupled receptors, membrane transporters, and enzymes. When used in a suitable dosage, these peptides may be useful *Address correspondence to this author at the Institute of Marine Sciences, therapeutics [8, 9]. In the pharmaceutical field, peptide tox- Federal University of Ceara, Ceara, Brazil; Tel: +55 85 3366 7001; ins can be used in their original form (natural or synthetic) or Fax: +55 85 3366 7002; E-mails: [email protected]; [email protected] 1873-4316/20 $65.00+.00 © 2020 Bentham Science Publishers Current Pharmaceutical Biotechnology 98 Current Pharmaceutical Biotechnology, 2020, Vol. 21, No. 2 dos Santos et al. a chemically modified form, mimicking the desired action of in an unmodified and active form. Moreover, the presence of the original peptide [2]. proteinases in the digestive system rapidly causes the amide bonds of peptides to break down, contributing to their low In this context, drugs derived from venom peptides or stability in vivo. All these facts preclude the oral administra- protein toxins were approved by the Food and Drug Admin- istration (FDA, U.S. Department of Health and Human Ser- tion of peptides, which is the most favorable route acceptable by patients, in detriment to much less convenient invasive vices) for treatment of diverse clinical conditions, including alternatives [18]. Even if peptides can reach the bloodstream diabetes, hypertension, and chronic pain. Several venom- in certain cases, they are degraded rapidly by various circu- derived peptides are also in preclinical development, while lating proteases, or even eliminated from the body by the others are under clinical studies that have the potential to hepatic and renal systems. This chemical instability is related treat a range of diseases, including cancer and autoimmune diseases [10]. Examples of venom-derived peptides and to the individual structure of each peptide, such as stabiliza- tion by post-translational modification. Linear peptides pharmaceuticals prepared from venom-peptide leads ap- (without disulfide bonds or other covalent constraints) are proved by the FDA that are in current clinical use are sum- more susceptible to proteolysis and more rapidly degraded marized in Table 1. Although a relatively high number of in vivo [17]. These characteristics could decrease the half-life peptides and proteins have been isolated from animal ven- of peptides in the bloodstream and, consequently, require oms, such numbers reflect only a small part of the huge chemical diversity found in marine and venomous terrestrial repetitive administration to obtain their therapeutic effects when in use. Repetitive drug administration is an undesirable organisms. It has been argued that there exists a practically regimen for patients and contributes to decreased compliance infinite potentiality to be explored in the field of venom pep- with a given treatment [19]. Apart from these barriers, toxici- tides and derivatives [9, 10]. ty may also be associated with the use of venom peptides as Considering that many current therapies are deficient, the pharmaceuticals, especially the antimicrobial and cytolytic importance of animal venoms as innovative resources for peptides. These classes of peptides, expressed in the venom drug discovery becomes clear when noting therapeutic pep- and venom glands of snakes, scorpions, bees, wasps and oth- tides are highly selective pharmacological agents. Despite er animals can display an off-target effect causing cytotoxici- the exceptional potential for drug discovery and develop- ty and damage to diverse biological systems [17, 20-24]. ment, several limitations have been reported for this class of High toxicity to humans imposes, in some circumstances, the compounds, hampering the process of converting venom discontinuation of venom peptides in clinical trials of drug peptides into therapeutic agents. The low stability, short half- development platforms [25]. life, and poor oral bioavailability are some of these barriers. Considering these facts, some strategies have been de- Toxicity can often also be a limiting factor, capable of revised to overcome these drawbacks, to advance the devel- stricting the development of new drugs. A promising strategy opment of venom peptides for therapeutic purposes. Cycliza- that has been developed to overcome these drawbacks is the tion, for example, is a technique that has been tested to in- use of nanocarriers for delivery and improve the bioavailability of venom peptides [11, 12]. Previous reports have em- crease the resistance of peptides to proteolysis. Alternatively, PEGylation and covalent binding to larger proteins, as well phasized the importance of nanostructures to deliver toxins as the incorporation of peptides into slow release polymer and animal venoms for diverse

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