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ACS Biomaterials Science & Engineering Aug 2021Bolaamphiphile, which is a class of amphiphilic molecules, has a unique structure of two hydrophilic head groups at the ends of the hydrophobic center. Peptidic... (Review)
Review
Bolaamphiphile, which is a class of amphiphilic molecules, has a unique structure of two hydrophilic head groups at the ends of the hydrophobic center. Peptidic bolaamphiphiles that employ peptides or amino acids as their hydrophilic groups exhibit unique biochemical activities when they self-organize into supramolecular structures, which are not observed in a single molecule. The self-assembled peptidic bolaamphiphiles hold considerable promise for imitating proteins with biochemical activities, such as specific affinity toward heterogeneous substances, a catalytic activity similar to a metalloenzyme, physicochemical activity from harmonized amino acid segments, and the capability to encapsulate genes like a viral vector. These diverse activities give rise to large research interest in biomaterials engineering, along with the synthesis and characterization of the assembled structures. This review aims to address the recent progress in the applications of peptidic bolaamphiphile assemblies whose densely packed peptide motifs on their surface and their stacked hydrophobic centers exhibit unique protein-like activity and designer functionality, respectively.
Topics: Biomimetics; Furans; Peptides; Proteins; Pyridones
PubMed: 34309378
DOI: 10.1021/acsbiomaterials.1c00576 -
Trends in Biotechnology Feb 2017Peptidic biomaterials represent a particularly exciting topic in regenerative medicine. Peptidic scaffolds can be specifically designed for biomimetic customization for... (Review)
Review
Peptidic biomaterials represent a particularly exciting topic in regenerative medicine. Peptidic scaffolds can be specifically designed for biomimetic customization for targeted therapy. The field is at a pivotal point where preclinical research is being translated into clinics, so it is crucial to understand the theory and describe the status of this rapidly developing technology. In this review, we highlight major advantages and current limitations of self-assembling peptide-based biomaterials, and we discuss the most widely used classes of assembling peptides, describing recent and promising approaches in tissue engineering, drug delivery, and clinics. We also suggest design strategies and hurdles that still need to be overcome to fully exploit their therapeutic potential.
Topics: Biomimetic Materials; Extracellular Matrix; Nanocapsules; Peptides; Protein Binding; Tissue Engineering; Tissue Scaffolds
PubMed: 27717599
DOI: 10.1016/j.tibtech.2016.09.004 -
Methods in Molecular Biology (Clifton,... 2019Macrocyclic peptides are a unique class of molecules that display a relatively constrained peptidic backbone as compared to their linear counterparts leading to the... (Review)
Review
Macrocyclic peptides are a unique class of molecules that display a relatively constrained peptidic backbone as compared to their linear counterparts leading to the defined 3-D orientation of the constituent amino acids (pharmacophore). Although they are attractive candidates for lead discovery owing to the unique conformational features, their peptidic backbone is susceptible to proteolytic cleavage in various biological fluids that compromise their efficacy. In this chapter we review the various classical and contemporary chemical and biological approaches that have been utilized to combat the metabolic instability of macrocyclic peptides. We note that any chemical modification that helps in providing either local or global conformational rigidity to these macrocyclic peptides aids in improving their metabolic stability typically by slowing the cleavage kinetics by the proteases.
Topics: Administration, Oral; Conotoxins; Cyclization; Cyclotides; High-Throughput Screening Assays; Kinetics; Methylation; Molecular Conformation; Peptide Hormones; Peptides, Cyclic; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand
PubMed: 31134565
DOI: 10.1007/978-1-4939-9504-2_2 -
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 -
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 -
Advanced Healthcare Materials May 2019Wound healing is a multifaceted biological process involving the replacement of damaged tissues and cellular structures, restoring the skin barrier's function, and... (Review)
Review
Wound healing is a multifaceted biological process involving the replacement of damaged tissues and cellular structures, restoring the skin barrier's function, and maintaining internal homeostasis. Over the past two decades, numerous approaches are undertaken to improve the quality and healing rate of complex acute and chronic wounds, including synthetic and natural polymeric scaffolds, skin grafts, and supramolecular hydrogels. In this context, this review assesses the advantages and drawbacks of various types of supramolecular hydrogels including both polymeric and peptide-based hydrogels for wound healing applications. The molecular design features of natural and synthetic polymers are examined, as well as therapeutic-based and drug-free peptide hydrogels, and the strategies for each system are analyzed to integrate key elements such as biocompatibility, bioactivity, stimuli-responsiveness, site specificity, biodegradability, and clearance.
Topics: Animals; Biocompatible Materials; Humans; Hydrogels; Peptides; Polymers; Tissue Engineering; Wound Healing
PubMed: 30835960
DOI: 10.1002/adhm.201900104 -
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 -
Chemical Reviews Nov 2019Dendrimers have attracted immense interest in science and technology due to their unique chemical structure that offers a myriad of opportunities for researchers.... (Review)
Review
Dendrimers have attracted immense interest in science and technology due to their unique chemical structure that offers a myriad of opportunities for researchers. Dendritic design allows us to present peptides in a branched three-dimensional fashion that eventually leads to a globular shape, thus mimicking globular proteins. Peptide dendrimers, unlike other classes of dendrimers, have immense applications in biomedical research due to their biological origin. The diversity of potential building blocks and innumerable possibilities for design, along with the fact that the area is relatively underexplored, make peptide dendrimers sought-after candidates for various applications. This review summarizes the stepwise evolution of peptidic dendrimers along with their multifaceted applications in various fields. Further, the introduction of biomacromolecules such as proteins to a dendritic scaffold, resulting in complex macromolecules with discrete molecular weights, is an altogether new addition to the area of organic chemistry. The synthesis of highly complex and fully folded biomacromolecules on a dendritic scaffold requires expertise in synthetic organic chemistry and biology. Presently, there are only a handful of examples of protein dendrimers; we believe that these limited examples will fuel further research in this area.
Topics: Amino Acid Sequence; Animals; Antiviral Agents; Cross-Sectional Studies; Dendrimers; Drug Carriers; Humans; Peptides; Proteins
PubMed: 31556597
DOI: 10.1021/acs.chemrev.9b00153 -
Methods in Molecular Biology (Clifton,... 2019This review describes a selection of macrocyclic natural products and structurally modified analogs containing peptidic and non-peptidic elements as structural features... (Review)
Review
This review describes a selection of macrocyclic natural products and structurally modified analogs containing peptidic and non-peptidic elements as structural features that potentially modulate cellular permeability. Examples range from exclusively peptidic structures like cyclosporin A or phepropeptins to compounds with mostly non-peptidic character, such as telomestatin or largazole. Furthermore, semisynthetic approaches and synthesis platforms to generate general and focused libraries of compounds at the interface of cyclic peptides and non-peptidic macrocycles are discussed.
Topics: Biological Products; Cyclization; Depsipeptides; Humans; Lactones; Macrocyclic Compounds; Oxazoles; Peptide Library; Peptides, Cyclic; Permeability; Protein Conformation; Spiro Compounds; Streptogramins; Thiazoles
PubMed: 31134572
DOI: 10.1007/978-1-4939-9504-2_9