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  • Cell-penetrating Peptides and their Therapeutic Potential

    Cell-penetrating peptides, also known as CPP, have the ability to cross plasma membranes. Ever since the discovery of this ability, it has been exploited for a variety of applications, including delivering bioactive molecules to stop the actions of diseases producing cellular mechanisms.

    Through the selective delivery of drugs into the target cells, it is possible to achieve improved drug distribution, as well as a significant reduction of dosing and toxicity. In this review, we will look at some of the challenges being encountered in this specific field of application, as well as some of the factors that may influence the efficacy of the delivery.

    About Cell-penetrating peptides

    Cell-penetrating peptides feature short peptide sequences – usually made up to 30 amino acids in length. They have the unique feature of being able to go through the cellular membranes from where they can be equipped to deliver a variety of cargo. The very first discovery regarding cell-penetrating peptides, was in the antennapedia homeodomain protein and the HIV-1 TAT proteins.

    This was due to the fact that these two protein types have the unique ability to enter inside of the cells. Following the discovery, the specific domains responsible for the cellular uptake were isolated, giving rise to a new group of transfection molecules, known as cell-penetrating peptides, which are also known as protein transduction domains, PTDs.

    The very first cell-penetrating peptides were obtained from existing proteins, but with time, scientists and researchers have made attempts to modify the peptide sequences for greater efficacy. The main reason for doing so, was to remove the minimal functional domains, and to bring in expression vectors with very minimal interferences to the cloning capabilities of the vector.

    The next step was to create a chimeric peptide, which featured cell-penetrating regions from wasp venom, also known as galanin protein. The last class of the cell-penetrating peptides featured the construction of a synthetic peptide that had better or improved cell penetration capabilities. Examples of these peptides include polyarginine, as well as some improved versions of the natural cell-penetrating peptides.

    Cell-penetrating peptides have proven to be very effective in delivering a variety of cargo into the cells. These include, but are not limited to small therapeutic molecules, and large cargoes such as plasmids and proteins. They are known to have an extraordinary ability that makes them ideal candidates for both research and therapeutic applications.

    Subtle evidence to this fact, is the increase in the use of the cell-penetrating peptides in lots of therapeutic applications, in fields such as antineoplastic therapies, and antimicrobial applications. Additionally, there are lots of CPP-based treatments and therapies that have already gone through clinical trials, and are being seen as very powerful, and potent delivery methods for a wide range of therapeutic agents.

    The use of cell-penetrating peptides is due to the numerous advantages they have over other delivery methods. Currently, gene delivery vectors are mainly classified into either vector or non-vector deliveries. Both of these categories are widely used in a variety of applications, though viral vectors have always shown very high rates of gene expression and replication. However, they are seen not to come with certain biological threats.

    There is also a great variation in non-viral delivery methods – they range from electroporation and microinjection to chemical approaches, such as calcium phosphate and cationic liposomes.

    Of all these methods, it can be claimed that cell-penetrating peptides have given some of the most outstanding results when it comes to transinfections, with very high transinfection rates, as well as the versatility to be used in a wide variety of cell types.

    Also, they have been demonstrated to have reduced cellular toxicity, which has made it possible for transinfection to be carried out via very simple methodologies.

    The chemistry of cell-penetrating peptides

    The very first cell-penetrating peptides to be used in active research were obtained from the sequences of membrane-interacting proteins, such as antimicrobial peptides, fusion proteins, transmembrane domains, and signal peptides. From these proteins, it was possible to identify short sequences that had the unique capability to efficiently cross over most of the cellular membranes.

    The process of translocation happened in a carrier or a receptor-dependent method, which made it possible for the delivery of biomolecules and other cargo right inside the intracellular compartments.

    One of the proteins – TAT from the HIV-1 virus, was realized to have the properties to behave like a carrier mediating the transportation of various cargo molecules through the plasma membranes of both in vivo and in vitro cells.

    This unique ability to penetrate the plasmas membranes was later on associated with a very specific domain of the HIV-1 virus, and it was duly designated as PTD. Peptides with similar capabilities have also been designated as PTDs.

    There are various other peptides that are known to have the ability to move across plasma membranes, and a good number of them have been found to have several arginine residues. It is critical to note that most of the polyarginine peptides have demonstrated very good rates of cellular uptakes. This unique ability of transduction, has been closely associated with the effects of the guanidinium groups usually found in the arginine residues.

    It has also been noted that arginine oligomers have the ability to form bidentate bonds. These bonds are usually typical of the guanidinium groups. Studies show that the bonds may be the very initial steps in the transduction process. You should remember that the cellular association of guanidinium groups is not necessarily the only mechanism that is usually used to initiate the cellular uptake.

    There are other well-documented initiation mechanisms that have been proven by the cell-penetrating peptides, and these mechanisms don’t contain arginine residues. However, transportation can still be done into the cells, just with the same efficiency as with the polyarginine.

    However, from only the basic nature of peptides, there is not enough information to formulate a detailed explanation of the efficiency of translocation. One of the challenges with this, is that lysime-rich peptides have been known to possess highly reduced translocation efficiency in comparison to arginine-rich peptides. Conversely, some cargo poly-lysine peptides have been shown to have very high transduction efficiency.

    Chemical modifications of cell-penetrating peptides

    There are various alterations that can be done to cell-penetrating peptides with the alterations not being limited to the modifications of the amino acid’s functional groups in the peptide chain. It is very possible to substitute the amino acids to come up with a customized hydrophobicity, new cationic content, as well as other properties that will suit certain specific applications. In one in vitro study where a library of 15 amino-acid long viral peptides was used, it was observed that there was enhanced translocation efficiency with low concentrations.

    This was mainly attributed to the presence of cationic amino acids. A common modification to the cell-penetrating peptides, may include replacing an existing residue with another residue that has a stronger affinity for the cell surface.

    A typical example of such a modification could be substituting lysine for arginine. Another interesting modification to cell-penetrating peptides, is the use of histidine. This is because histidine is known to provide an acidic endosomal escape through what is commonly known as proton sponge effect.

    There are other approaches that can greatly enhance the availability of the cell-penetrating peptides to deliver cargo, and this includes modifying the functional groups in the peptide. This is usually done through the formation of linkages or masking groups to highly active sites.

    In most cases, the newly created bond should be easily broken under normal physiological conditions to make it possible to obtain the original CPP.

    Through this approach, it was possible to modify the model amphipathic peptide using citraconic anhydride, which was used to block the e-amino group of the lysine residues. This was achieved through the formation of an acid labile amide group.

    With the masking of the cationic charge of model amphipathic peptide, a notable decrease was realized in the non-specific binding and uptake. Additionally, it was observed that a series of peptides based on the TP10 peptide could be modified chemically using stearic acid. Such a modification led to an increase in the uptake and it also improved the endossomolytic properties.

    Mechanisms of cell penetrations

    There are various mechanisms through which cell-penetrating peptides are able to make the journey across the plasma membranes. They include, but are not limited to the following:

    Endosomal and non-endosomal pathways
    There have been debates on how the cell-penetrating peptides enter the cells for more than two decades now. Initially, metabolic energy-independent pathways were proposed to be the am in the mechanism, but this notion was soon dropped when studies showed that the cell-penetrating peptides could enter the cells through an energy-independent endocytosis mechanism.

    Endocytosis has always been suggested as being one of the main internalization routes for many of the complex cell-penetrating peptides. As a result, there are so many endocytotic pathways that have been advanced to facilitate the uptake of complex peptides.

    Interestingly, most of the cell-penetrating peptide complexes don’t just rely on one route to gain entry into the cells since they have the ability to use a variety of endocytic pathways at the same time. This has made the study of its entry mechanism a very detailed and complex process than it was initially considered.

    The latest developments in this field tend to suggest that there is another mechanism that the cell-penetrating peptides use to go through the cell membranes. Apart from the normal physical translocation of the membrane, cell-penetrating peptides also have the ability to enter the cells via induction of endocytotic-like membrane invaginations – a process also known as physical endocytosis.

    Different cell-penetrating peptides may have the ability to induce tubular structures or negative curvatures on the membranes, for non-artificial membranes. This type of entry is relatively new since it was just recently discovered.

    According to this theory, it seems as though the cell-penetrating peptides start by binding to phospholipids before starting to form a negative curvature in the cellular membrane without using any of the cellular metabolic energy. Consequently, invagination starts to grow inwards until it is cleaved with dynamin, in a process that is very similar to cellular endocytosis.

    Endocytotic release of conjugates

    Endosomal escape is usually the very next step after the process of internalization of cell-penetrating peptides through endocytosis. This process must always take place to stop the cell-penetrating hormones as well as the cargoes from being degraded in lysosomes. There have been numerous proposals for modification strategies aimed at facilitating the escape of the cell-penetrating hormones from the endosomes.
    Some of these proposals include adding endosome-disruptive sequences, acidifying the endosmotic membranes, and including molecules such as chloroquine to the sequence of the cell-penetrating peptides.

    Sadly, the endocytic escape rate can be quite difficult to examine due to the cargo biological effects that may happen much later than the actual time of the cargo release from the endosome. In essence, it is possible for the cargo markers to show activity when they are still right within the endosomes.

    To overcome this problem, scientists have created a fluorescent marker – CPP conjugate. This conjugate is bound by a disulfide bridge designed to impede fluorescence. This disulfide bridge is usually cleaved by plasmatic enzymes after the endosomal escape, giving room for the free marker to start emitting fluorescence, which is then possible to measure.

    Through this method, it was observed that the results of cargo delivery by the cell-penetrating peptides can be as fast as ten minutes, and may reach a peak after thirty minutes. After this, the rate at which the molecule penetrates the cell membranes will be lower than the number of molecules being degraded.

    Once the cytoplasm is reached, it is a must for the cargo complexes to be released. This can happen through cleavage or dissociation of the complexes. The mode chosen will always depend on the type of bond used in linking the cell-penetrating peptides to the cargo.

    Cell-penetrating Peptides and their Therapeutic Potential


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  • Peptides as the Next Generation Solution for Anti-Infectives

    The presence of large-scale manufacturing and advanced synthesis technologies have currently made it possible for the production of even the most complex peptide anti-infectives.

    With the possibility of this class of molecules being seen as the next-gen of infectives, safe anti-microbial, as well as with a better understanding of pharmacology and biology, it is just a matter of time before we see the introduction into clinical trials for these promising drug candidates.

    This is a vital step in the history and life cycle of peptide anti-infectives and it is one of the strongest indications that the therapeutic and commercial potential of the anti-infectives, is about to be achieved.
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  • The Development and Use of Peptides as Therapeutics

    Peptides refer to biologically active molecules that contain at least two amino acids, interlinked by a peptide bond. Unlike large proteins, they are small in size and a typical chain will usually not go past 100 amino acids.

    Since peptides are highly selective and also known to have relatively safe characteristics, their pharmacological profiles have always appealed to the research world. They are readily available in the human body where they play diverse biological roles.

    For most applications, they mainly act as regulatory and signaling molecules in various physiological processes. Back in the day, the instability of peptides limited their use in the design and development of human drugs, but due to technological breakthroughs, the instability challenges have all been overcome, greatly increasing the broad application of peptides.
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  • The Use of Therapeutic Peptides in Cancer Treatments

    Cancer and cardiovascular diseases are among the major causes of death in most developed countries. Most of the conventional approaches to treating cancer are quickly losing their therapeutic relevance due to the lack of tumor selectivity, drug resistance, and solubility. As such, there is a great need for the development of new therapeutic agents and treatment plans. Over the years, therapeutic peptides have provided a glimmer of hope, and they are currently being considered as a novel approach to treating a variety of diseases, including various forms of cancer.

    This is because they come with a variety of advantages over normal proteins and antibodies. Some of these advantages include easy synthesis, high target selectivity, and specificity, and very low toxicity. They, however, have some drawbacks, with their stability and short half-life being among major concerns. In this piece, we will be looking at some of the therapeutic peptides receiving the most attention currently and some of the strategies being used to overcome some of the peptide limitations.
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  • Promising Cancer Therapies With Peptide-Based Treatments

    Peptides are molecules consisting of various chains of amino acids joined by peptide bonds through the process of a dehydration-condensation reaction. There are various places, or various origins of peptides, including but not limited to direct synthesis by the body, artificial synthesis, or through processes such as proteolysis. They play a huge role in the treatment of a variety of diseases, and they are currently at the center stage in the development of various types of vaccines.

    Diseases such as allergic reactions, asthma, fibrosis, autoimmune diseases, and infectious diseases have been some of the greatest beneficiaries of peptide-based therapies. There are several advantages that make peptide therapies preferred in the treatment of a variety of diseases. Some of these benefits include the fact that they are easily available, easy to purify and store. Some of the therapies have undergone both in vitro and in vivo testing, with a lot of promising outcomes. There are also several studies continuing to look into how peptides can be used as effective therapies for a variety of conditions.
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  • Interesting Findings About Peptide Immunotherapeutics

    The development of peptide vaccines has been in the works for a very long time, but with minimal success. However, advancement in medical technology, as well as an increased understanding of the immune system – more specifically the operations of the antigenic epitopes in stimulating an immune response, have opened a whole new field and made the development of peptide vaccines possible. Peptide-based vaccines – technically known as epitope ensemble vaccines, are viewed as a viable alternative approach to the discovery and development of not just disease-specific therapeutics but also prophylactic vaccines.

    These vaccines are very different from the other types of vaccines or moieties, which usually use dead or attenuated whole pathogens in the formulation of the vaccines. With this approach, epitopes are viewed as the relevant parts of the antigens commonly referred to as B and/or T cells mediating adaptive immunity. As such, the most promising epitope vaccine ensemble is those that feature desirable B and T cell-mediated immune responses. Also, with peptide-based vaccines, the risks of starting a pathogenic reaction or other undesirable off-target responses are much lower compared to the conventional vaccines. This, hence, brings a lot of credence to these vaccines are they are seen to be safer and more effective compared to the conventional vaccines.
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  • Peptides as Therapeutic Agents for Inflammatory-Related Diseases

    An inflammation is the body's normal response to lesions and infections. The immune system cells move to the site of the injury or infection, and cause an inflammation. To treat this disorder, unspecific small molecule drugs are used, which may cause some side effects.
    The inflammation produces mediators such as cytokines, interleukins, and growth factors. It is necessary to regulate the inflammation to stabilize or heal the damaged cells or tissues.

    A lot of research is being made, and peptides have been used as an alternative anti-inflammatory therapy. Actually, peptides are considered effective compounds, and show an innovative strategy by stopping, diminishing, and/or changing the expression and activity of mediators.
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  • What are the benefits of peptides in cosmetics ?

    The cosmetic industry represents a huge worldwide sector. Between skincare, makeup, and haircare, it is growing faster than most other industries, and its market value is estimated to be worth almost $805 billion by 2023.

    The key to this evolution is innovation. Every brand tries to create new products with new compositions in order to target a maximum of people. More and more people are very careful about each product’s contents, which is why brands always have to conduct lots of research and find a way to make the perfect product, containing the best natural elements possible.
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  • Antimicrobial Peptides in Human Health

    The human body has always been special to scientists because it has this amazing capacity to repair itself (like a broken bone) and to protect itself from any kind of exterior aggressions. After studies and a lot of research, it was discovered that peptides in the body are one of the reasons why it can face pathogens and stay healthy.

    One kind of peptide is very important in the body, which is the antimicrobial peptide (AMP). These peptides are essential to the body's natural defense against diseases. They ward off invading microbial pathogens such as viruses and bacteria. Also, they have had a major role in the development of therapeutic agents to prevent and treat diseases, which has become even more important, considering the situation we are facing now.
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  • The Potential of Antifungal Peptides as Therapeutic Agents

    Fungi have been used for centuries for food and beverage processing. In recent years, a better understanding of science and advancement in medical technology has shone a spotlight on their potential of being used as antibiotics to overcome the well-known deficits of the current antibiotics in use. However, it should not be forgotten that fungi are also responsible for causing a myriad of human infections. There is well-documented evidence of an increase in the number of cases for community-acquired fungal infections over the last decade.

    Also, a rise in the number of immunodeficiency-related cases, antibiotic resistance development, and limited therapeutic options have made the search for alternatives a serious concern, and one which the research world is currently heavily involved with. There is a need for the new antifungals being formulated currently to be less toxic for the host, and it is also vital for them to have broader or targeted antimicrobial spectra, and have very little chances for triggering resistance in the long run.
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