Current Pharmaceutical Biotechnology - Volume 12, Issue 8, 2011

Peptides own a high potential in the field of cancer because of their high target selectivity and vast applications. Tumor targeted drug delivery has increasingly become an essential step in anticancer therapies as conventional chemotherapies are accompanied with several limitations such as adverse effects and development of drug resistance. Among many targeting approaches, peptide-based carrier systems have contributed utmost in tumor targeting. Peptides have been substantially used in delivery of therapeutic drugs and genes to tumor and tumor-associated cells. In addition, conjugation of imaging probes to the tumor-specific peptides or peptide-based carriers promoted their application for tumor diagnostics. Peptides themselves can also serve as anticancer agents. Peptides can be rationally designed for their high selectivity to a target and can be easily produced with chemical or recombinant techniques. In addition, peptides have lower/no immunogenicity, higher tissue permeability, and stronger affinity to the receptors compared to other targeting agents such as monoclonal antibodies. This special issue focuses on the peptide designing with novel methods and application of the peptides in tumor targeted delivery as well as their potential use as anticancer agents. Designing of peptides can be approached by various methods such as in silico and Phage-display methods. In this issue, Sadatmousavi and coworkers have included many peptide-designing methods in their article on self-assembling peptides and enlisted a range of peptides derived from these methods. As a part of a review on anti-angiogenic peptides, Rosca and coworkers have also contributed a special section on computational approaches for peptide discovery. To have a focus on peptide discovery, Pirogova and coworkers have introduced a novel method of Resonant Recognition model (RRM) to design the bioactive peptides. RRM frequencies represent the characteristic features of different proteins biological functions and interactions to their targets. Examples of peptide mimicking IL-12 activity and an antagonistic peptide for bFGF have been presented in this paper including bioactivity analyses of RRM-IL-12 peptide. Tumor targeted delivery of anticancer drugs is highly challenging as several barriers have to be crossed in order to reach in tumors. During tumor development, tumor cells recruit new blood vessels through neoangiogenesis and supply nutrition to the tumor. Corti and Curnis have contributed an interesting review on the targeting to tumor vasculature using NGR peptide against CD13. Many variables of this peptide were synthesized and used for delivery of chemotherapeutic agents, cytokines, viral particles, nucleic acids. Authors have published many research articles in this area and also summarized their potential findings in this review. Garg and Kokkoli, in this issue, have contributed a research article in which they experimentally demonstrated the application of a fibronectin-mimetic peptide for tumor targeting to α5β1 integrin. The α5β1 integrin is a transmembrane protein that is expressed on many tumor types and mediates interaction between adjacent cells and/or the extracellular matrix. This peptide was conjugated to pH-sensitive PEGylated liposomes that control the release of encapsulated drug within lysosomes where pH drops down. They also showed that peptide can induce intracellular delivery of calcein-loaded liposomes and the loaded drug could be released in short time. These data demonstrate that peptides can be applied to bring large carriers into tumor cells. Tumors derived from reproductive organs such as ovarian, prostate, breast and endometrial express hormonal receptors that are specifically expressed on tumor cells of these organs. Zhang and Xu have focused their review on the application of hormone peptides in tumor targeting. They have thoroughly discussed the application of the peptides binding to the receptors for luteinizing hormone-releasing hormone (LHRH), follicle-stimulating hormones (FSH), and luteinizing hormone (LH). Application of these peptides in delivering anticancer agents or siRNA either by direct conjugation or with the help of a carrier has been discussed in detail. In addition to the above mentioned tumor targeting peptides, Sadatmousavi and coworkers have presented an excellent review on the role of self-assembling peptides in tumor targeting. Self-assembling peptide have been potentially used as carriers for drug/gene delivery. They can be rationally tuned to form a variety of stable nanostructures e.g. fibers, rods, tubes, nanovesicles and globules. Self-assembling peptides include peptide amphiphile, bolaamphiphile peptides, cyclic peptides and ioniccomplementary peptides are the main classes. These peptides can form β-sheet, α-helix and random coil secondary structures and can respond to change in pH, temperature, and ionic strength by altering their macromolecular structure. Tumor environment has a lower pH due to hypoxia and higher temperature than normal tissue, and these stimuli therefore make selfassembling peptides an interesting agent for providing controlled release of therapeutic agents within tumors. Authors have significantly extended the research area, and this review summarizes their and others' research work. Intracellular delivery of therapeutic proteins, nucleic acids, and polymers is a major hurdle for their effectivity. Receptormediated internalization is one of the processes for intracellular delivery but yet limited by the endosomal escaping barriers for some agents such as small RNA. Potential role of the receptor binding peptides has already been discussed above. Other type of peptides are cell penetrating peptides (CPP) which facilitate the intracellular delivery in a different manner. In this issue, Choi and coworkers have contributed an excellent review on CPP and their applications in tumor targeting. This review includes the detailed information on different types of CPP such as TAT, penetratin, transportan, pep-1 and many others which used so far in tumor field. They have described mechanism of action of these peptides including some practical details. Many sections of this article explain the potential utility of CPP in intracellular delivery of therapeutic proteins, siRNA and polymeric drugs into tumor cells. One can appreciate the elaborated figures explaining the mechanisms in an easy way as well as detailed text providing the up-to-date information on the literature over these therapeutic agents. Use of peptides is not limited to tumor targeted delivery but they can themselves serve as anticancer agents. This issue comprises two articles focused on peptide application as therapeutic agents. Barras and Widmann have contributed a detailed review on the apoptosis-inducing peptides for cancer therapy. During apoptosis, cells undergo shrinking and cleave their DNA and make apoptotic bodies which follows with their disposal by phagocytes or other cells. Induction of this process in tumor cells can generate tumor therapeutics. Balance between pro-apoptotic and anti-apoptotic factors lead to the decision of cell death, which is mainly controlled by Bcl-2 family proteins and some other regulatory proteins such as IAP, Smac and p53. Authors have meticulously described the peptides derived from Bcl-2 family (Bak, PUMA, Bad, Bid, Bim), IAPs- and Smacderived and p53-derived peptides as well as many natural peptides. Formation of tumor vasculature (angiogenesis) is the most essential process for tumor growth without which the tumor cannot grow. Therefore, interruption in this process using anti-angiogenic peptides can lead to the inhibition of tumor growth. The group of Prof. Popel has significantly contributed to the field of anti-angiogenic peptides and added an excellent review on the same topic in this issue (Rosca et al). They have comprehensively enlisted the peptides that have been shown to suppress tumor angiogenesis in pre-clinical models or are in clinical stages. Angiogenesis is a complex process in which tumor cells recruit endothelial cells by releasing growth factors and chemokines. These recruited cells interact with extracellular matrix (ECM) protein through their integrin receptors and complete blood vessels formation. This cascade can be interfered at various stages using peptides derived from the participating proteins. Rosca and colleagues have nicely presented anti-angiogenic peptides based on their origin e.g. ECM, growth factors, chemokines, coagulation factors etc. Not limited to this, authors have included a large section on designing and optimization of anti-angiogenic peptides for cancer applications. Developing these peptides to pharmaceutical product is the next biggest challenge, and a strategic development plan and possible solutions to overcome many associated problems have also been discussed. In summary, this special issue provides a comprehensive knowledge on the applications of peptides for tumor targeting and as anticancer therapies.

This review focuses on the application of two classes of peptides, i.e., self-assembling peptides (SAPs) and cell-targeting peptides (CTPs), in the development of nanocarrier delivery systems. Self-assembling peptides are emerging in a wide range of biomedical and bioengineering applications and fall into several classes, including peptide amphiphilies, bolaamphiphile peptides, cyclic peptides, and ionic complementary peptides, which can be found naturally or synthesized. The advantage of synthesizing peptides is that their self-assembling properties can be exploited to form desirable structures for various applications. Another, unique property of self-assembling peptides, is stimuli-responsibility in different environments including various pHs, temperatures, ionic strengths, etc. These characteristics make peptides applicable in a wide range of biomaterials in drug discovery. This study reviews the design principles of well-known selfassembling peptides, as well as their physical/chemical properties. In addition, it discusses the therapeutic cancer-targeting peptides and current combinatorial peptide library methods used to identify targeting peptides. Cancer-targeting peptides can target either tumor cell surfaces or tumor vasculature. The RGD peptide is one of the first tumor-targeting peptides that can bind to self-assembling peptides or any other nanocarrier to improve the therapeutic efficiency of targeting drug delivery systems.

Peptides have emerged as important therapeutics that are being rigorously tested in angiogenesis-dependent diseases due to their low toxicity and high specificity. Since the discovery of endogenous proteins and protein fragments that inhibit microvessel formation (thrombospondin, endostatin) several peptides have shown promise in pre-clinical and clinical studies for cancer. Peptides have been derived from thrombospondin, collagens, chemokines, coagulation cascade proteins, growth factors, and other classes of proteins and target different receptors. Here we survey recent developments for anti-angiogenic peptides with length not exceeding 50 amino acid residues that have shown activity in pre-clinical models of cancer or have been tested in clinical trials; some of the peptides have been modified and optimized, e.g., through L-to-D and non-natural amino acid substitutions. We highlight technological advances in peptide discovery and optimization including computational and bioinformatics tools and novel experimental techniques.

Drug discovery and development are intense, lengthy and interdisciplinary processes. Traditionally, drugs were discovered by synthesizing compounds in time-consuming multi-step experimental investigations followed by in vitro and in vivo biological screening. Promising candidates were then further studied for their pharmacokinetic properties, metabolism and potential toxicity. Today, the process of drug discovery has been revolutionized due to the advances in genomics, proteomics, and bioinformatics. Efficient technologies such as combinatorial chemistry, high throughput screening (HTS), virtual screening, de novo design and structure-based drug design contribute greatly to drug discovery. Peptides are emerging as a novel class of drugs for cancer therapy, and many efforts have been made to develop peptide-based pharmacologically active compounds. This paper presents a review of current advances and novel approaches in experimental and computational drug discovery and design. We also present a novel bioactive peptide analogue, designed using the Resonant Recognition Model (RRM), and discuss its potential use for cancer therapeutics.

Various peptide sequences have been discovered by selecting peptide-phage display libraries in vitro against specific receptors or in vivo in tumor-bearing animals. One class of these peptides is characterized by the presence of Asn- Gly-Asp (NGR), a structural motif that can recognize the endothelium and other cells of neoangiogenic vessels. Because of this property these peptides have been used by several investigators to deliver a variety of drugs, cytokines, nanoparticles, viruses and imaging agents to tumor blood vessels. Here we review the reports on these conjugates and discuss the structural, functional and stability properties of NGR embedded into different molecular scaffolds.

pH-sensitive liposomes undergo rapid destabilization under mildly acidic conditions such as those found in endocytotic vesicles. Though this makes them promising drug carriers, their application is limited due to their rapid clearance from circulation by the reticulo-endothelial system. Researchers have therefore used pH-sensitive liposomes that are sterically stabilized by polyethylene glycol (PEG) molecules (stealth liposomes) on the liposome surface. The goal of this study is to bring bio-functionality to pH-sensitive PEGylated liposomes in order to facilitate their potential use as a targeted drug delivery agent. To improve the selectivity of these nanoparticles, we included a targeting moiety, PR_b which specifically recognizes and binds to integrin α5β1 expressing cells. PR_b (KSSPHSRN(SG)5RGDSP) is a novel fibronectin- mimetic peptide sequence that mimics the cell adhesion domain of fibronectin. Integrin α5β1 is expressed on several types of cancer cells, including colon cancer, and plays an important role in tumor growth and metastasis. We have thoroughly studied the release of calcein from pH-sensitive PEGylated liposomes by varying the lipid composition of the liposomes in the absence and presence of the targeting peptide, PR_b, and accounting for the first time for the effect of both pH and time (photo-bleaching effect) on the fluorescence signal of calcein. We have demonstrated that we can design PR_b-targeted pH-sensitive PEGylated liposomes, which can undergo destabilization under mildly acidic conditions and have shown that incorporating the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b targeted pH-sensitive PEGylated liposomes bind to CT26.WT colon carcinoma cells that express integrin α5β1, undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. Our studies demonstrate that PR_b-functionalized pH-sensitive targeted delivery systems have the potential to deliver a payload directly to cancer cells in an efficient and specific manner.

Targeted therapy may be a promising approach against cancer because its focus of attention is to enhance the efficacy and to reduce the side effects of antitumor agents through high selectivity. One of targeted strategies is to use tumor- specific ligands as targeting moieties to carry drugs into tumor cells, and use the receptors that expressed on tumor cells as target sites to bind with peptide ligands. The fact that the distributions of reproductive hormone receptors are relatively limited in normal tissues makes it possible to use them as targeted sites and use hormone peptides as targeting moieties for cancer treatment. Until now many tumor targeting approaches with reproductive hormone peptides have been developed, and some of them have been introduced into clinical trials. Here a review is given to discuss the targeted antitumor therapeutic strategies based on gonadotropin-releasing hormone, follicle-stimulating hormones, luteinizing hormone, human chorionic gonadotropin and their receptors.

Until recently, most research efforts aimed at developing anti-cancer tools were focusing on small molecules. Alternative compounds are now being increasingly assessed for their potential anti-cancer properties, including peptides and their derivatives. One earlier limitation to the use of peptides was their limited capacity to cross membranes but this limitation was alleviated with the characterization of cell-permeable sequences. Additionally, means are designed to target peptides to malignant cells. Most anti-cancer peptidic compounds induce apoptosis of tumor cells by modulating the activity of Bcl-2 family members that control the release of death factors from the mitochondria or by inhibiting negative regulators of caspases, the proteases that mediate the apoptotic response in cells. Some of these peptides have been shown to inhibit the growth of tumors in mouse models. Hopefully, pro-apoptotic anti-tumor peptides will soon be tested for their efficacy in patients with cancers.

Anticancer drug delivery has been hindered due to cell membrane permeability and the lack of a selective marker for tumor cells. Cell permeability is related to the bioavailability of drugs and has therefore been considered to be an essential step for achieving therapeutic efficacy. While different types of transporters currently exist, cell penetrating peptides (CPPs) have become one of the most popular and effective tools for intracellular drug delivery. Most of the original CPPs are short peptides with basic residues. The mechanism of CPP cell entry remains to be established; however, the CPPs can deliver any type of molecular cargo including solid nanoparticles. Herein, this paper will discuss the classification of CPPs, the mechanism of cell entry, the application of CPPs in tumor therapy, and recent advances in targeted cell penetration that involve CPPs.

From a pragmatic perspective, we are all familiar with the clinical need for antibiotics, and many of us understand the role that antibiotics play in maintaining a safe and abundant food supply. However, the study of antibiotics has also contributed to our fundamental understanding of microbial physiology, which has given us wonderful insights into our own physiology. Antimicrobial “mechanisms of action” and antimicrobial resistance studies have furthered our understanding of cell wall synthesis, membrane physiology, cell transport, and other essential enzymatic processes within the microbe. Discovery of antimicrobials has enhanced our understanding of organismal chemistry leading to the discovery of novel enzymes that have potential biotechnological applications for the synthesis of novel compounds. Furthermore, antimicrobials are being utilized in material industrial applications for coating products preventing microbial contamination and biofilm formation in a wide variety of consumer products. Moreover, antimicrobials are now being investigated and utilized for their anticancer and antiviral properties. Antimicrobial research has provided more opportunity for economic growth than any other form of research, while simultaneously providing an enormous amount of knowledge about the world we live in. Although there isn't enough space to touch on all the aspects described above, these reviews do provide the reader with an enormous amount of knowledge and understanding with regard to antimicrobial research and its potential for meeting the challenges ahead. The study of antimicrobial peptides has aided in our understanding of membrane-peptide interactions and membrane physiology. Mohamed Amiche et al. discuss membranotrope activity of antimicrobial peptides, in particular dermaseptins. Futhermore, resistance to antibiotics that target cell wall synthesis is a serious concern for the future treatment of bacterial infections. Marimuthu Jeya et al. discuss efforts that have been made to produce semisynthetic glycopeptides, in particular teicoplanin, with improved pharmacokinetic and pharmacodynamic properties and activity towards resistant strains. These studies provide insight into mechanisms of resistance and cell wall physiology. Bacteriocins from lactic acid bacteria (LAB) and the bacteriocin-producing organisms have been presented by Manuel Montalban- Lopez et al. A wide array of applications ranging from the use of the antibiotic in treating bacterial, fungal, and viral infections to the potential use of the antibiotic producing organism as a probiotic has been presented by the authors. Dr. Kenji Sonomoto's group has presented two reviews on lantibiotics in the area of bioengineering and immunity. Lantibiotics are ribosomally synthesized antibiotics that undergo extensive post translational modifications. Dr. Sonomoto provides a review of the in vitro and in vivo approaches used to produce an active lantibiotic. Furthermore, in the second review, they show that immunity is highly specific to the lantibiotic produced by the lantibiotic producing organism, while methods of immunity vary from pumping to sequestering the lantibiotic. From this review, it is easy to see that the methods for producing lantibiotics as well as the resistance mechanisms of the lantibiotic producing organism are as interesting as the lantibiotic peptide. Given the recent publicized outbreaks of foodborne infections in the United States, food safety has become a serious concern. Min Li et al. offer a review describing natural antimicrobials used in the food industry and their potential for minimizing or eliminating foodborne Staphylococcus aureus (S. aureus) illnesses. A wide array of natural compounds that has significant potential for ensuring a higher level of food safety is described. Their mode of action, bacterial resistance, chemical structure, effectiveness, synergistic effects and future prospects are discussed. In the realm of antifungal research, two reviews are presented. Bing Zhai and Xiaorong Lin present a review in which they describe the potential use of several FDA-approved drugs that were not intended to have antifungal activity for treating fungal infections. In addition, they summarize the mechanism of action and chemical composition of newly discovered antifungal compound and their potential for future therapeutic use. David Tschorner et al. identified more than eighty antifungal peptides in which they have characterized their physiochemical characteristics and activities. Through a structural and functional approach the authors provide a review that may aid in the development of new antimicrobial peptides with improved therapeutic potential. The development of antibiotics has played a major role in increasing our life expectancy and quality of life since the middle of the 20th century. While we do face future challenges in maintaining our advantage over microbial infections and food sustainability, antibiotic research will continue to provide solutions and teach us more about the world we live in.

Antimicrobial peptides (AMPs) produced by a wide variety of organisms are major actors of the host defense systems against invading pathogenic microorganisms. These peptides exhibit a broad spectrum of action against bacteria, yeasts, fungi, protozoa and viruses. It is widely believed that a large part of their antimicrobial effect derives from direct interactions with the lipid membrane surrounding the target cells, causing its permeabilization and cell lysis. However, the exact nature of these interactions is presently unclear. The skin of the amphibians has proved to be a remarkably rich storehouse of AMPs that encompass a wide variety of structural motifs. This natural AMP bank is used in combined approaches, based on biophysical and cellular biology methods, to elucidate how these peptides perturb the membrane and whether such membrane perturbations are related to the antimicrobial activity of these peptides. Here we review our current knowledge about the structure and the mechanism of action of the dermaseptin super-family, α-helical amphipathic AMPs isolated from the skin of frogs of the Phyllomedusa genus. Dermaseptins are genetically related, with a remarkable identity in signal sequences and acidic propieces of their preproforms but have clearly diverged to yield several families of microbicidal cationic peptides that are structurally distinct. Particularly, we focused on the orthologous peptides dermaseptin S and B of which the shortening from the carboxy terminal extremity causes a drastic change in their membrane disruption activity. These peptides could be good models to study the membrane-peptide interactions discussed in this review.

Glycopeptide antibiotics, vancomycin and teicoplanin, inhibit cell wall synthesis in Gram-positive bacteria by interacting with peptidoglycan D-Ala-D-Ala peptide stem termini of the pentapeptide side chains of the peptidoglycan precursors. In glycopeptide-resistant bacteria, multiresistance poses major therapeutic problems. New potent antibacterial agents are needed to combat these resistance problems, resulting in the explosion of novel glycopeptides in recent years. The glycosylation patterns of glycopeptides and the chemical modifications of the glycosyl moieties greatly influence their antibiotic activity, and certain combinations have resulted in highly active new compounds. Considerable efforts have been made to produce semisynthetic glycopeptides with improved pharmacokinetic and pharmacodynamic properties and activity towards resistant strains. This review provides an overview of the chemistry, the antimicrobial activity, the pharmacokinetics and the toxicology of teicoplanin and other glycopeptide antibiotic derivatives.

Bacteriocins are ribosomally synthesized (poly)peptides produced by almost all prokaryotic lineages. Bacteriocins from lactic acid bacteria (LAB) and bacteriocin-producer probiotic organisms have been thoroughly studied due to their wide spectra of action, the long-term use in food fermentations and the consideration of these microorganisms as beneficial for human beings. Most of the studies on the biotechnological application of diverse bacteriocins have been focused on their use as food preservatives, nisin being the prototype successfully used in alimentation. However, bacteriocins from LAB have demonstrated a remarkable potential as therapeutics for medical or veterinary uses, alone or in combination with classical antimicrobials. Their interest is even higher now that the resistance to the antibacterials used in therapeutics is growing. In this review we explore exciting opportunities for bacteriocin and probiotic applications, highlighting the possibilities for new and innovative research in order to give the necessary attention to this type of natural molecules that exhibit a great potential.

Lantibiotics are ribosomally synthesized, post-translationally modified, peptide antibiotics containing unusual amino acids such as dehydrated amino acids and lanthionine. These unusual amino acids impose conformational constraints on the peptide and contribute to the biological activity and high physicochemical stability of lantibiotics. Recent researches on the modification enzymes responsible for dehydration and cyclization have considerably increased our understanding of their molecular characteristics and relaxed specificity. These insights enabled us to exploit these modification enzymes for developing new lantibiotic variants with improved therapeutic potential. Several methodologies have been explored to engineer novel lantibiotics. Here, we outline the current knowledge of modification enzymes. We also describe the methodologies and strategies used to engineer lantibiotics and provide some examples of successful generation of lantibiotics with enhanced activity.

Lantibiotics are posttranslationally modified antimicrobial peptides produced by some Gram-positive bacteria. After secreting mature lantibiotics, producer cells are at risk for self-destruction. Lantibiotic-producing strains express immunity protein(s) to protect cells against their own products. To date, several types of immunity proteins with diverse structures and functions have been identified. These proteins consist of ABC transporters, lipoproteins, membraneassociated peptides, and transmembrane proteins. The ABC transporters for lantibiotic immunity export membraneassociated lantibiotics to the extracellular space by using ATP hydrolysis as a driving force. Lipoproteins and some membrane proteins for lantibiotic immunity interact with lantibiotics. Some lantibiotic producers equip themselves with 2 immunity systems, which function differently but work synergistically. The immunity levels conferred by lantibiotic immunity proteins are highly specific to their original lantibiotics and structurally related analogues. This review outlines structures and molecular functions of lantibiotic immunity proteins.

Staphylococcus aureus (S. aureus) is an important foodborne and environmental pathogen that can produce toxins in foods and cause infections in soft tissues. S. aureus that have developed resistance to the conventional antimicrobials are commonly called Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant S. aureus (VRSA). Their prevalence is believed to be due to the widespread use of antibiotics. Therefore, natural antimicrobials are in urgent demand as alternatives to conventional antibiotics to treat S. aureus infections. In this review, natural antimicrobials from plant, animal and microbiological origins are discussed, including their mode of action and mechanisms of bacterial resistance, major components, chemical structure, effectiveness, synergistic effects and future prospects.

Invasive fungal infections are a serious threat to public health, particularly to people with compromised or suppressed immunity. Although the current antifungal therapies have been significantly improved, the outcome is still far from satisfactory, partly due to the limited number of classes of clinically available antifungals, the development of resistance to current antifungals, and the challenges of proper and early diagnosis. Recent advances in the development of new antifungals, although still in the investigational stages, offer some new hope of improving the future of antifungal therapy. Here, we review literature regarding the antifungal activities of several FDA-approved drugs, which were originally intended for treating other conditions, as well as newly discovered natural/artificial compounds. We focus on their mechanisms of action, limitations, and potential in treating fungal infections. The diverse mechanisms of action of these compounds summarized here can provide new directions for future endeavors on antifungal drug development.

Many cationic peptides with antimicrobial properties have been isolated from bacteria, fungi, plants, and animals. These peptides vary in molecular size, potency and spectra of activities. This report surveyed the literature to highlight the peptides that have antifungal activity and greatest potential for development as new therapeutic agents. Thus, to be included in the evaluation, each peptide had to fulfil the following criteria: (i) potent antifungal activity, (ii) no, or minimal, mammalian cell toxicity, (iii) of ≤25 amino acids in length, which minimises the costs of synthesis, reduces immunogenicity and enhances bioavailability and stability in vivo, (iv) minimal post-translational modifications (also reduces the production costs). The ∼80 peptides that satisfied these criteria are discussed with respect to their structures, mechanisms of antimicrobial action and in vitro and in vivo toxicities. Certainly, some of these small peptides warrant further study and have potential for future exploitation as new antifungal agents.