Centipede venoms as a source of drug leads

ABSTRACT

Introduction: Centipedes are one of the oldest and most successful lineages of venomous terrestrial predators. Despite their use for centuries in traditional medicine, centipede venoms remain poorly studied. However, recent work indicates that centipede venoms are highly complex chemical arsenals that are rich in disulfide-constrained peptides that have novel pharmacology and three-dimensional structure.

Areas covered: This review summarizes what is currently known about centipede venom proteins, with a focus on disulfide-rich peptides that have novel or unexpected pharmacology that might be useful from a therapeutic perspective. The authors also highlight the remarkable diversity of constrained three-dimensional peptide scaffolds present in these venoms that might be useful for bioengineering of drug leads.

Expert opinion: Like most arthropod predators, centipede venoms are rich in peptides that target neuronal ion channels and receptors, but it is also becoming increasingly apparent that many of these peptides have novel or unexpected pharmacological properties with potential applications in drug discovery and development.     

Progress with peptide scanning to study structure-activity relationships: the implications for drug discovery

ABSTRACT

Introduction: Peptides have gained renewed interest as candidate therapeutics. However, to bring them to a broader clinical use, challenges such as the rational optimization of their pharmacological properties remain. Peptide scanning techniques offer a systematic framework to gain information on the functional role of individual amino acids of a peptide. Due to progress in mastering new chemical synthesis routes targeting amino acid backbone, they are currently diversified. Structure-activity relationship (SAR) analyses such as alanine- or enantioneric- scanning can now be supplemented by N-substitution, lactam cyclisation- or aza-amino scanning procedures addressing not only SAR considerations but also the peptide pharmacological properties.

Areas covered: This review highlights the different scanning techniques currently available and illustrates how they can impact drug discovery.

Expert opinion: Progress in peptide scanning techniques opens new perspectives for peptide drug development. It comes with the promise of a paradigm change in peptide drug design in which peptide drugs will be closer to the parent peptides. However, scanning still remains assimilable to a trial and error strategy that could benefit from being combined with specific in silico approaches that start reaching maturity.     

Stabilized helical peptides: overview of the technologies and therapeutic promises

Introduction: Helical structures in proteins and naturally occurring peptides play a major role in a variety of biological processes by mediating interactions with proteins and other macromolecules such as nucleic acids and lipid membranes. The use of short synthetic peptides encompassing helical segments to modulate or disrupt such interactions, when associated with human diseases, represents great pharmacological interest.

Areas covered: Multiple chemical approaches have been developed to increase the conformational and metabolic stabilities of helical peptides and to improve their biomedical potential. After a brief overview of these technologies and the most recent developments, this review will focus on the main therapeutic areas and targets and will discuss their promise.

Expert opinion: Potential benefits associated with increased helix stability extend beyond simple affinity enhancement. Some peptidomimetic helices are being endowed with features desirable for cellular activity such as increased resistance to proteolysis and/or cell permeability. Recent advances in the field of peptide and related peptidomimetic helices are not just conceptual, but are likely to be of practical utility in the process of optimizing peptides as clinical candidates, and developing medium-size therapeutics.     

Spider peptide toxins as leads for drug development

Venomous animals use a highly complex cocktails of proteins, peptides and small molecules to subdue and kill their prey. As such, venoms represent highly valuable combinatorial peptide libraries, displaying an extensive range of pharmacological activities, honed by natural selection. Modern analytical technologies enable us to take full advantage of this vast pharmacological cornucopia in the hunt for novel drug leads. Spider venoms represent a resource of several million peptides, which selectively target specific subtypes of ion channels. Structure–function studies of spider toxins are leading not only to the discovery of novel molecules, but also to novel therapeutic routes for cardiovascular diseases, cancer, neuromuscular diseases, pain and to a variety of other pathological conditions. This review presents an overview of spider peptide toxins as candidates for therapeutics and focuses on their applications in the discovery of novel mechanisms of analgesia.     

Conus Venoms: A Rich Source of Neuroactive Peptides

Abstract

Purification of toxins from the venoms of two fish-hunting gastropod cone snails, Conus geographus and Conus magus has revealed the presence of three classes of paralytic peptide toxins. These are: 1) the w-conotoxins, which block voltage activated calcium channels at the presynaptic terminus; 2) the α-conotoxins, which block the acetylcholine receptor and 3) the ω-conotoxins, which inhibit muscle sodium channels, and therefore prevent propagation of the muscle action potential. These toxins are basic peptides from 13–27 amino acids long, rich in cystine residues which are present as disulfides. A number of α-conotoxins and one a-conotoxin have been chemically synthesized.

In addition to the paralytic conotoxins, the venoms of Conus have other toxins which have not yet been completely characterized. A large number of neuroactive peptides and proteins have also been found. Since there are approximately 300 species of Conus, all of which produce venoms, the cone snails promise to be a rich source of neuroactive peptides in the years ahead.     

Novel peptide toxins recently isolated from sea anemones

Sea anemones are a rich source of peptide toxins acting on ion channels. Two classes of peptide toxins, site-3 sodium channel toxins and Kv1 potassium channel toxins, have been well characterized and some of them used as valuable pharmacological reagents. Recently, the following six peptides toxins, which structurally constitute a new family but target different ion channels, have been isolated: BDS-I and -II (Kv3 potassium channel toxins) from Anemonia sulcata, APETx1 (human ether-a-go-go-related gene potassium channel toxin) and APETx2 (acid-sensing sodium channel toxin) from Anthopleura elegantissima, BcIV (sodium channel toxin) from Bunodosoma caissarum and Am II (whose target is unknown) from Antheopsis maculata. In addition, the following structurally novel peptide toxins have also emerged in sea anemones: gigantoxin I (epidermal growth factor-like toxin) from Stichodactyla gigantea and acrorhagins I and II from acrorhagi (specialized aggressive organs) of Actinia equina. This review deals with the structural and functional features of these recently isolated sea anemone peptide toxins that are promising tools in studying the physiology of diverse ion channels.     

Function Prediction of Peptide Toxins with Sequence-Based Multi-Tasking PU Learning Method

Peptide toxins generally have extreme pharmacological activities and provide a rich source for the discovery of drug leads. However, determining the optimal activity of a new peptide can be a long and expensive process. In this study, peptide toxins were retrieved from Uniprot; three positive-unlabeled (PU) learning schemes, adaptive basis classifier, two-step method, and PU bagging were adopted to develop models for predicting the biological function of new peptide toxins. All three schemes were embedded with 14 machine learning classifiers. The prediction results of the adaptive base classifier and the two-step method were highly consistent. The models with top comprehensive performances were further optimized by feature selection and hyperparameter tuning, and the models were validated by making predictions for 61 three-finger toxins or the external HemoPI dataset. Biological functions that can be identified by these models include cardiotoxicity, vasoactivity, lipid binding, hemolysis, neurotoxicity, postsynaptic neurotoxicity, hypotension, and cytolysis, with relatively weak predictions for hemostasis and presynaptic neurotoxicity. These models are discovery-prediction tools for active peptide toxins and are expected to accelerate the development of peptide toxins as drugs.     

A comparison of peptide and folate receptor targeting of cancer cells: from single agent to nanoparticle

Introduction: There is broad interest in a targeted strategy that delivers a concentrated therapeutic payload to tumor cells, because of the significant potential for improvements in therapeutic outcomes and reduction of side effects if therapeutics can be delivered only to diseased tissue.

Areas covered: This review describes how the coupling chemistry and surface charge effects of peptide labeling in nanoparticle drug delivery strategies have proved difficult to control, resulting in many studies that use folate instead. However, the successful peptide targeting of structural, hormonal, cytokine and endocrine receptors in the delivery of therapeutic and diagnostic radionuclides provides a strong indication that it is worth finding methods to synthesize peptide-targeted nanoparticles.

Expert opinion: Chemical conjugation to peptides reduces colloidal stability, which is a limiting factor in the development of targeting nanoparticles. Mechanistic studies are needed in order to develop peptide targeting for nanoparticles to rival the selectivity that has been achieved with the small molecule folate. Although most of the work so far has been done using gold nanoparticles, biological and polymer nanoparticles are more colloidally stable and present enormous opportunities for coupling to peptides.     

Spider Venoms and Spider Toxins

Abstract

Spider venoms and toxins are useful tools for the study of ion channels and synaptic functions of neurons in vertebrates and invertebrates. The components of spider venom, such as proteins, peptides, polyamines and bioamines, are species-specific. The various functions of these toxins are reviewed in this paper.     

Ceramic nanocarriers: versatile nanosystem for protein and peptide delivery

Introduction: Proteins and peptides have been established to be the potential drug candidate for various human diseases. But, delivery of these therapeutic protein and peptides is still a challenge due to their several unfavorable properties. Nanotechnology is expanding as a promising tool for the efficient delivery of proteins and peptides. Among numerous nano-based carriers, ceramic nanoparticles have proven themselves as a unique carrier for protein and peptide delivery as they provide a more stable, bioavailable, readily manufacturable, and acceptable proteins and polypeptide formulation.

Areas covered: This article provides an overview of the various aspects of ceramic nanoparticles including their classification, methods of preparation, latest advances, and applications as protein and peptide delivery carriers.

Expert opinion: Ceramic nanocarriers seem to have potential for preserving structural integrity of proteins and peptides, thereby promoting a better therapeutic effect. This approach thus provides pharmaceutical scientists with a new hope for the delivery of proteins and peptides. Still, considerable study on ceramic nanocarrier is necessary with respect to pharmacokinetics, toxicology, and animal studies to confirm their efficiency as well as safety and to establish their clinical usefulness and scale-up to industrial level.     

Terpenes and derivatives as a new perspective for pain treatment: a patent review

Introduction: Terpenes are natural compounds found in several organisms belonging to the animal and plant kingdoms. They constitute the largest class of natural products with > 55,000 known compounds structurally diversified. Several studies have attributed to this big family of compounds a range of pharmacological properties, such as anticancer, antimicrobial, antifungal, antiviral, antihyperglycemic, analgesic, anti-inflammatory and antiparasitic.

Areas covered: In this review, the authors summarize therapeutic patent applications concerning the employment of terpenes for pain relief, focusing on the perspective for these compounds to become candidates for new drugs intended to control painful syndromes.

Expert opinion: Over years of tremendous academic and industrial investment in the characterization of the analgesic action of terpenes, there was the development of a successful product that has been well-accepted clinically. Furthermore, there is still hope that new therapeutic options for the control of painful syndromes will be developed from terpenes, which have been shown to be great candidates for this purpose because of the range of pharmacological mechanisms in important target sites.     

ImKTx88, a novel selective Kv1.3 channel blocker derived from the scorpion Isometrus maculates

Scorpion toxins are useful in the structure-function research of ion channels and valuable resources for drug design. The Kv1.3 channel is an important pharmacological target for the therapy of T cell-mediated autoimmune diseases, and many toxin peptides targeting Kv1.3 have been identified as good drug candidates in recent years. In this study, a novel toxin gene ImKTx88 was isolated from the venom of the scorpion Isometrus maculates through the construction of the cDNA library method, and the recombinant toxin peptide was purified and characterized physiologically. The mature peptide of ImKTx88 contained 39 amino acid residues including six cysteines and was predicted to be a new member of α-KTx scorpion family by sequence analysis. The electrophysiological experiments further indicated that the rImKTx88 peptide had a novel pharmacological profile: it inhibited Kv1.3 channel current with an IC₅₀ of 91 ± 42 pM, and exhibited very good selectivity for Kv1.3 over Kv1.1 (4200-fold) and Kv1.2 (93000-fold) channels, respectively. All these results suggested that, as a new selective Kv1.3 channel blocker, the ImKTx88 peptide may serve as a potential drug candidate in the therapy of autoimmune diseases.     

On the horizon: trophic peptide growth factors as therapy for neonatal short bowel syndrome

Introduction: Short bowel syndrome (SBS) occurs more commonly in human neonates than in adults. There are currently no approved therapeutic agents aimed directly at stimulating intestinal adaptation in this population.

Areas Covered: A brief review of SBS and intestinal adaptation is first presented. We then present candidate peptide growth factors that are suggested to augment intestinal adaptation in SBS, with a particular focus on glucagon-like peptide-2, as well as insulin-like growth factor-1 and epidermal growth factor. The normal physiology of these peptides and our understanding of their roles in intestinal adaptation are discussed. We further consider the roles of these peptides in the ontogeny of the gastrointestinal tract and we present the limited preclinical data on the effects of administering these peptides in neonatal SBS.

Expert Opinion: The clinical translation of trophic peptide therapies in neonatal SBS will require several challenges to be overcome. The optimal dose, timing and route of administration for the likely peptide, or combination of peptides, to be administered will be paramount. Despite their cost to patient care, trophic peptides have shown promise in preclinical models of neonatal SBS and may be especially beneficial for neonates that lack remnant ileum and suffer from irreversible intestinal failure.     

Spider-venom peptides that target voltage-gated sodium channels: Pharmacological tools and potential therapeutic leads

Voltage-gated sodium (Na_V) channels play a central role in the propagation of action potentials in excitable cells in both humans and insects. Many venomous animals have therefore evolved toxins that modulate the activity of Na_V channels in order to subdue their prey and deter predators. Spider venoms in particular are rich in Na_V channel modulators, with one-third of all known ion channel toxins from spider venoms acting on Na_V channels. Here we review the landscape of spider-venom peptides that have so far been described to target vertebrate or invertebrate Na_V channels. These peptides fall into 12 distinct families based on their primary structure and cysteine scaffold. Some of these peptides have become useful pharmacological tools, while others have potential as therapeutic leads because they target specific Na_V channel subtypes that are considered to be important analgesic targets. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides and so far only 0.01% of this diversity been characterised. Thus, it is likely that future research will reveal additional structural classes of spider-venom peptides that target Na_V channels.     

Discovery and optimization of peptide macrocycles

ABSTRACT

Introduction: Macrocyclic peptides are generally more resistant to proteolysis and often have higher potency than linear peptides and so they are excellent leads in drug design. Their study is significant because they offer potential as a new generation of drugs that are potent and specific, and thus might have fewer side effects than traditional small molecule drugs.

Areas covered: This article covers macrocyclic drug leads based on nature-derived cyclic peptides as well as synthetic cyclic peptides and close derivatives. The natural peptides include cyclotides, sunflower-derived peptides, theta-defensins and orbitides. Technologies to make engineered cyclic peptides covered here include cyclization via amino acid linkers, CLIPS, templates, and stapled peptides.

Expert opinion: Macrocyclic peptides are promising drug leads and several are in clinical trials. The authors believe they offer key advantages over traditional small molecule drugs, as well as some advantages over protein-based ‘biologics’ such as antibodies or growth factors. These include the ability to penetrate cells and attack intracellular targets such as protein-protein interactions as well as to hit extracellular targets. Some macrocyclic peptides such as cyclotides offer the potential for production in plants, thus reducing manufacture costs and potentially increasing opportunities for their distribution to developing countries at low cost.     

Recent CPP-based applications in medicine

ABSTRACT

Introduction: Cell-penetrating peptides (CPP) offer versatile tools for the field of drug delivery and development of macromolecular therapeutics. These tools have matured into applications that allow the use of proteins, nucleic acid, peptides, imaging agents, and low molecular weight drugs as therapeutic entities.

Areas covered: The progress of the field is discussed in the current review, with the examples from a recent couple of years, in the utilization of CPPs in medicine. Specific focus is on the research articles that include applications that have direct translational value. Progress with protein mimicry and its recent leap in medicine is discussed with special attention, but also achievements with nanoformulation and drug targeting is presented.

Expert opinion: The opinion section discusses some of the limitations and shortcomings, proposing the areas where more effort should be invested in order to increase the translational value of the current preclinical research.     

Pharmacology of spider venom toxins

Abstract

Spider venom is an intricate combination of target specific enzymatic and non-enzymatic toxins. In addition, the venom also contains polyamine neurotoxins, ATP, AMP, ADP, guanosine, 2,4,6-trihydroxy purine, γ-aminobutyric acid, glutamic acid, aspartic acid, taurine, histamine, serotonin, tyramine, octomine, nor-adrenaline and inorganic salts. Several enzymes such as hyaluronidase, protease, phospholipase D, sphingomyelinase and neurotoxic peptides have been extensively characterized from spider venoms. Spider bite is an accidental event; envenomation can cause both local (edema, hemorrhage, myo/dermonecrosis) and systemic toxicity (neurotoxicity, myotoxicity, cytotoxicity and hemostatic alterations). While, the latter is pertaining to the very few groups of spiders, namely, Loxosceles species and Hippasa partita. The local and systemic toxicity may be attributed to the synergistic effect of both enzymatic and non-enzymatic toxins. More importantly, spider venom components possess immense potential for biotechnological and therapeutic applications. In addition, they have also been used as prototypes in drug design. Based on these facts, this review makes an attempt to provide an insight into the pharmacology of enzymatic toxins (Sphingomyelinase, Hyaluronidase, Phospholipase, Protease, Collagenase, Phosphodiesterase, ATPases, Alkaline phosphatase and Peptide isomerases) and non-enzymatic toxins (translationally controlled tumor proteins and serine protease inhibitors).