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Life Sciences Sep 2019Peptides are oligomers of amino acids, which have been used in a wide range of applications, particularly in medical and pharmaceutical sciences. Linear peptides have... (Review)
Review
Peptides are oligomers of amino acids, which have been used in a wide range of applications, particularly in medical and pharmaceutical sciences. Linear peptides have been extensively developed in various fields of medicine as therapeutics or targeting agents. The branched structure of peptide dendrimers with peptide (commonly, poly l‑Lysine) or non-peptide (commonly poly‑amidoamine) core, often exhibits valuable novel features, improves stability and enhances the functionality of peptide in comparison with small linear peptides. The potential applications of Branched and hyper-branched peptidic structures which are known as peptide dendrimers in biomedical sciences have been approved vastly. A peptide dendrimer contains three distinct parts including core, building blocks and branching units or surface functional groups. These structures provide a lot of opportunities in the pharmaceutical field, particularly for novel drug development. In this review, a brief summary of different biomedical applications of peptide dendrimers is presented, and peptide dendrimers as active pharmaceutical ingredients and drug delivery carriers are discussed. Applications of peptide dendrimers in vaccines and diagnostic tools are also presented, in brief. Generally, peptide dendrimers are promising biomaterials with high evolution rate for clinical and non-clinical applications in medicine.
Topics: Biocompatible Materials; Biotechnology; Dendrimers; Drug Carriers; Drug Delivery Systems; Humans; Peptide Fragments
PubMed: 31415768
DOI: 10.1016/j.lfs.2019.116754 -
Angewandte Chemie (International Ed. in... Jul 2019Using peptide assemblies with emergent properties to achieve elaborate functions has attracted increasing attention in recent years. Besides tailoring the self-assembly... (Review)
Review
Using peptide assemblies with emergent properties to achieve elaborate functions has attracted increasing attention in recent years. Besides tailoring the self-assembly of peptides in vitro, peptide research is advancing into a new and exciting frontier: the rational design of peptide assemblies (or their derivatives) for biological functions in a complex environment. This Minireview highlights recent developments in peptide assemblies and their applications in biological systems. After introducing the unique merits of peptide assemblies, we discuss the recent progress in designing peptides (or peptide derivatives) for self-assembly with conformational control. Then, we describe biological functions of peptide assemblies, with an emphasis on approach-instructed assembly for spatiotemporal control of peptide assemblies, in the cellular context. Finally, we discuss the future promises and challenges of this exciting area of chemistry.
Topics: Humans; Molecular Structure; Particle Size; Peptides; Protein Conformation; Surface Properties
PubMed: 30903643
DOI: 10.1002/anie.201814552 -
International Journal of Molecular... Jun 2023In the modern scientific landscape, natriuretic peptides are a complex and interesting network of molecules playing pleiotropic effects on many organs and tissues,... (Review)
Review
In the modern scientific landscape, natriuretic peptides are a complex and interesting network of molecules playing pleiotropic effects on many organs and tissues, ensuring the maintenance of homeostasis mainly in the cardiovascular system and regulating the water-salt balance. The characterization of their receptors, the understanding of the molecular mechanisms through which they exert their action, and the discovery of new peptides in the last period have made it possible to increasingly feature the physiological and pathophysiological role of the members of this family, also allowing to hypothesize the possible settings for using these molecules for therapeutic purposes. This literature review traces the history of the discovery and characterization of the key players among the natriuretic peptides, the scientific trials performed to ascertain their physiological role, and the applications of this knowledge in the clinical field, leaving a glimpse of new and exciting possibilities for their use in the treatment of diseases.
Topics: Atrial Natriuretic Factor; Natriuretic Peptides; Peptides; Vasodilator Agents; Natriuretic Peptide, Brain
PubMed: 37298592
DOI: 10.3390/ijms24119642 -
Methods in Molecular Biology (Clifton,... 2022Protein-protein interactions play crucial and subtle roles in many biological processes and modifications of their fine mechanisms generally result in severe diseases.... (Review)
Review
Protein-protein interactions play crucial and subtle roles in many biological processes and modifications of their fine mechanisms generally result in severe diseases. Peptide derivatives are very promising therapeutic agents for modulating protein-protein associations with sizes and specificities between those of small compounds and antibodies. For the same reasons, rational design of peptide-based inhibitors naturally borrows and combines computational methods from both protein-ligand and protein-protein research fields. In this chapter, we aim to provide an overview of computational tools and approaches used for identifying and optimizing peptides that target protein-protein interfaces with high affinity and specificity. We hope that this review will help to implement appropriate in silico strategies for peptide-based drug design that builds on available information for the systems of interest.
Topics: Biophysical Phenomena; Ligands; Peptides; Proteins
PubMed: 35298816
DOI: 10.1007/978-1-0716-1855-4_11 -
Drug Delivery Dec 2023Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to... (Review)
Review
Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to this day, incurable. As potential therapeutic drugs, peptides have many favorable chemical and pharmacological properties, starting with their great diversity, through their high affinity for binding to all sort of natural receptors, and ending with the various pathways of their breakdown, which produces nothing but amino acids that are nontoxic to the body. Despite these and other advantages, however, they also have their pitfalls. One of these disadvantages is the very low stability of natural peptides. They have a short half-life and tend to be cleared from the organism very quickly. Their instability in the gastrointestinal tract, makes it impossible to administer peptidic drugs orally. To achieve the best pharmacologic effect, it is desirable to look for ways of modifying peptides that enable the use of these substances as pharmaceuticals. There are many ways to modify peptides. Herein we summarize the approaches that are currently in use, including lipidization, PEGylation, glycosylation and others, focusing on lipidization. We describe how individual types of lipidization are achieved and describe their advantages and drawbacks. Peptide modifications are performed with the goal of reaching a longer half-life, reducing immunogenicity and improving bioavailability. In the case of neuropeptides, lipidization aids their activity in the central nervous system after the peripheral administration. At the end of our review, we summarize all lipidized peptide-based drugs that are currently on the market.
Topics: Peptides; Lipids
PubMed: 38010881
DOI: 10.1080/10717544.2023.2284685 -
Biophysical Journal Jun 2024Diffusion determines the turnover of biomolecules in liquid-liquid phase-separated condensates. We considered the mean square displacement and thus the diffusion...
Diffusion determines the turnover of biomolecules in liquid-liquid phase-separated condensates. We considered the mean square displacement and thus the diffusion constant for simple model systems of peptides GGGGG, GGQGG, and GGVGG in aqueous solutions after phase separation by simulating atomic-level models. These solutions readily separate into aqueous and peptide-rich droplet phases. We noted the effect of the peptides being in a solvated, surface, or droplet state on the peptide's diffusion coefficients. Both sequence and peptide conformational distribution were found to influence diffusion and condensate turnover in these systems, with sequence dominating the magnitude of the differences. We found that the most compact structures for each sequence diffused the fastest in the peptide-rich condensate phase. This model result may have implications for turnover dynamics in signaling systems.
Topics: Diffusion; Peptides; Biomolecular Condensates; Amino Acid Sequence; Water; Models, Molecular; Protein Conformation
PubMed: 38751116
DOI: 10.1016/j.bpj.2024.05.009 -
Accounts of Chemical Research May 2021Biological membranes separate the interior of cells or cellular compartments from their outer environments. This barrier function of membranes can be disrupted by... (Review)
Review
Biological membranes separate the interior of cells or cellular compartments from their outer environments. This barrier function of membranes can be disrupted by membrane-active peptides, some of which can spontaneously penetrate through the membranes or open leaky transmembrane pores. However, the origin of their activity/toxicity is not sufficiently understood for the development of more potent peptides. To this day, there are no design rules that would be generally valid, and the role of individual amino acids tends to be sequence-specific.In this Account, we describe recent progress in understanding the design principles that govern the activity of membrane-active peptides. We focus on α-helical amphiphilic peptides and their ability to (1) translocate across phospholipid bilayers, (2) form transmembrane pores, or (3) act synergistically, i.e., to produce a significantly more potent effect in a mixture than the individual components.We refined the description of peptide translocation using computer simulations and demonstrated the effect of selected residues. Our simulations showed the necessity to explicitly include charged residues in the translocation description to correctly sample the membrane perturbations they can cause. Using this description, we calculated the translocation of helical peptides with and without the kink induced by the proline/glycine residue. The presence of the kink had no effect on the translocation barrier, but it decreased the peptide affinity to the membrane and reduced the peptide stability inside the membrane. Interestingly, the effects were mainly caused by the peptide's increased polarity, not the higher flexibility of the kink.Flexibility plays a crucial role in pore formation and affects distinct pore structures in different ways. The presence of a kink destabilizes barrel-stave pores, because the kink prevents the tight packing of peptides in the bundle, which is characteristic of the barrel-stave structure. In contrast, the kink facilitates the formation of toroidal pores, where the peptides are only loosely arranged and do not need to closely assemble. The exact position of the kink in the sequence further determines the preferred arrangement of peptides in the pore, i.e., an hourglass or U-shaped structure. In addition, we demonstrated that two self-associated (via termini) helical peptides could mimic the behavior of peptides with a helix-kink-helix motif.Finally, we review the recent findings on the peptide synergism of the archetypal mixture of Magainin 2 and PGLa peptides. We focused on a bacterial plasma membrane mimic that contains negatively charged lipids and lipids with negative intrinsic curvature. We showed that the synergistic action of peptides was highly dependent on the lipid composition. When the lipid composition and peptide/lipid ratios were changed, the systems exhibited more complex behavior than just the previously reported pore formation. We observed membrane adhesion, fusion, and even the formation of the sponge phase in this regime. Furthermore, enhanced adhesion/partitioning to the membrane was reported to be caused by lipid-induced peptide aggregation.In conclusion, the provided molecular insight into the complex behavior of membrane-active peptides provides clues for the design and modification of antimicrobial peptides or toxins.
Topics: Cell Membrane; Lipids; Peptides; Protein Conformation, alpha-Helical
PubMed: 33844916
DOI: 10.1021/acs.accounts.1c00047 -
Journal of Chemical Theory and... Jun 2022PSD-95/discs-large/ZO-1 (PDZ) domains form a large family of adaptor proteins that bind to the C-terminal tails of their binding partner proteins. Via extensive...
PSD-95/discs-large/ZO-1 (PDZ) domains form a large family of adaptor proteins that bind to the C-terminal tails of their binding partner proteins. Via extensive molecular dynamics simulations and alchemical free energy calculations, we characterized the binding modi of phosphorylated and unphosphorylated EQVSAV peptides and of a EQVEAV phosphate mimic to the hPTP1E PDZ2 and MAGI1 PDZ1 domains. The simulations reproduced the well-known binding characteristics such as tight coordination of the peptidic carboxyl tail and pronounced hydrogen bonding between the peptide backbone and the backbone atoms of a β-sheet in PDZ. Overall, coordination by hPTP1E PDZ2 appeared tighter than by MAGI1 PDZ1. Simulations of wild-type PDZ and arginine mutants suggest that contacts with Arg79/85 in hPTP1E/MAGI1 are more important for the EQVEAV peptide than for EQVSAV. Alchemical free energy calculations and PaCS-MD simulations could well reproduce the difference in binding free energy between unphosphorylated EQVSAV and EQVEAV peptides and the absolute binding free energy of EQVSAV. However, likely due to small force field inaccuracies, the simulations erroneously favored binding of the phosphorylated peptide instead of its unphosphorylated counterpart, which is in contrast to the experiment.
Topics: Amino Acid Sequence; Carrier Proteins; Hydrogen Bonding; Molecular Dynamics Simulation; PDZ Domains; Peptides; Protein Binding
PubMed: 35608157
DOI: 10.1021/acs.jctc.1c01140 -
Langmuir : the ACS Journal of Surfaces... Nov 2022The safe and efficient delivery of nucleic acids including DNA, mRNA, siRNA, and miRNA into targeted cells is critical for gene therapy. Currently, viral gene vectors... (Review)
Review
The safe and efficient delivery of nucleic acids including DNA, mRNA, siRNA, and miRNA into targeted cells is critical for gene therapy. Currently, viral gene vectors are very popular, but they have potential toxicity and insecurity. Therefore, the development of nonviral vectors has attracted considerable research attention. Peptide assemblies are superior candidates for being used as gene vectors by having good biocompatibility, versatile molecular design, excellent assembly capacity, ease of modification, and stimuli responsivity. The de novo designed peptides not only can induce efficient condensation of nucleic acids into compacted nanoparticles and protect them from enzymatic digestion but also can effectively overcome biological barriers and improve gene delivery efficiency through targeted delivery, enhanced cellular uptake, improved endolysosomal escape, and nuclear importation. By having these merits, peptidic gene vectors are developing fast, showing outstanding advantages compared to liposome and polymer vectors. This Perspective focuses on peptidic gene delivery systems by emphasizing the molecular design strategies for meeting the criteria of gene condensation, protection from nuclease degradation, cellular uptake, endolysosomal escape, and so on. The new arising research area of peptide-based artificial viruses for gene and ribonucleoprotein delivery has also been reviewed. The challenges and future perspectives are put forward, aiming to provide a conclusive guide for the development of peptidic delivery systems to achieve efficient gene therapy.
Topics: Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Nucleic Acids; Peptides
PubMed: 36318179
DOI: 10.1021/acs.langmuir.2c02197 -
Angewandte Chemie (International Ed. in... May 2021Proteolysis of proteins and peptides is involved in the infection of cells by enveloped viruses and also in the invasion and spread of cancer cells. Shutting down...
Proteolysis of proteins and peptides is involved in the infection of cells by enveloped viruses and also in the invasion and spread of cancer cells. Shutting down broad-specificity proteases, however, is problematic because normal functions by these proteases will be affected. Herein, nanoparticle receptors were prepared from molecular imprinting for complex biological peptides. Their strong and selective binding enabled them to protect their targeted sequences from proteolysis in aqueous solution at stoichiometric amounts. Generality of the method was demonstrated by the protection of hydrophobic and hydrophilic peptides from different proteases, selective protection of a segment of a long peptide, and selective protection of a targeted peptide in a mixture. Most interestingly, two receptors targeting different parts of a long peptide could work in cooperation to protect the overall sequence, highlighting the versatility of the method.
Topics: Peptide Hydrolases; Peptides; Proteolysis
PubMed: 33725413
DOI: 10.1002/anie.202102148