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Drug Discovery Today Jan 2015Peptides are recognized for being highly selective and efficacious and, at the same time, relatively safe and well tolerated. Consequently, there is an increased... (Review)
Review
Peptides are recognized for being highly selective and efficacious and, at the same time, relatively safe and well tolerated. Consequently, there is an increased interest in peptides in pharmaceutical research and development (R&D), and approximately 140 peptide therapeutics are currently being evaluated in clinical trials. Given that the low-hanging fruits in the form of obvious peptide targets have already been picked, it has now become necessary to explore new routes beyond traditional peptide design. Examples of such approaches are multifunctional and cell penetrating peptides, as well as peptide drug conjugates. Here, we discuss the current status, strengths, and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development.
Topics: Animals; Drug Design; Half-Life; Humans; Peptides; Pharmaceutical Preparations
PubMed: 25450771
DOI: 10.1016/j.drudis.2014.10.003 -
Cells Oct 2021Peptides are increasingly being developed for use as therapeutics to treat many ailments, including cancer. Therapeutic peptides have the advantages of target... (Review)
Review
Peptides are increasingly being developed for use as therapeutics to treat many ailments, including cancer. Therapeutic peptides have the advantages of target specificity and low toxicity. The anticancer effects of a peptide can be the direct result of the peptide binding its intended target, or the peptide may be conjugated to a chemotherapy drug or radionuclide and used to target the agent to cancer cells. Peptides can be targeted to proteins on the cell surface, where the peptide-protein interaction can initiate internalization of the complex, or the peptide can be designed to directly cross the cell membrane. Peptides can induce cell death by numerous mechanisms including membrane disruption and subsequent necrosis, apoptosis, tumor angiogenesis inhibition, immune regulation, disruption of cell signaling pathways, cell cycle regulation, DNA repair pathways, or cell death pathways. Although using peptides as therapeutics has many advantages, peptides have the disadvantage of being easily degraded by proteases once administered and, depending on the mode of administration, often have difficulty being adsorbed into the blood stream. In this review, we discuss strategies recently developed to overcome these obstacles of peptide delivery and bioavailability. In addition, we present many examples of peptides developed to fight cancer.
Topics: Cell-Penetrating Peptides; Humans; Models, Biological; Nanoparticles; Neoplasms; Peptides; Proliferating Cell Nuclear Antigen
PubMed: 34831131
DOI: 10.3390/cells10112908 -
The Neuroscientist : a Review Journal... Dec 2021Humans are an unusually prosocial species, who engage in social behaviors that include altruism-whereby an individual engages in costly or risky acts to improve the... (Review)
Review
Humans are an unusually prosocial species, who engage in social behaviors that include altruism-whereby an individual engages in costly or risky acts to improve the welfare of another person-care, and cooperation. Current perspectives on the neurobiology of human prosociality suggest that it is deeply rooted in the neuroendocrine architecture of the social brain and emphasize the modulatory role of the neuropeptide hormone oxytocin. In this review, we provide a conceptual overview of the neurobiology of prosocial behavior with a focus on oxytocin's modulatory role in human prosociality. Specifically, we aim to encourage a better understanding of the peptide's susceptibility to diverse factors that produce heterogeneity in outcomes and the resulting methodological implications for measuring the behavioral effects of oxytocin in humans. After providing an overview of the state-of-the-art research on oxytocin's exogenous use, we elaborate on the peptide's modulatory role in the context of care-based altruism, cooperation, and conflict and discuss its potential for therapeutic interventions in psychiatric disorders characterized by social dysfunction.
Topics: Altruism; Humans; Mental Disorders; Oxytocin; Social Behavior
PubMed: 32981445
DOI: 10.1177/1073858420960111 -
Journal of Dental Research Mar 2017More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic... (Review)
Review
More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide's structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.
Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Proteins; Biofilms; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Host-Pathogen Interactions; Humans; Microbial Sensitivity Tests; Microbial Viability; Signal Transduction; Structure-Activity Relationship; Surface Properties
PubMed: 27872334
DOI: 10.1177/0022034516679973 -
Bioorganic & Medicinal Chemistry Jun 2018Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United... (Review)
Review
Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other major markets, and peptides continue to enter clinical development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chemistry efforts. We maintain a comprehensive dataset on peptides that have entered human clinical studies that includes over 150 peptides in active development today. Here we provide an overview of the peptide therapeutic landscape, including historical perspectives, molecular characteristics, regulatory benchmarks, and a therapeutic area breakdown.
Topics: Animals; Drug Approval; Drug Discovery; Drug Evaluation; Humans; Molecular Targeted Therapy; Peptides
PubMed: 28720325
DOI: 10.1016/j.bmc.2017.06.052 -
Methods in Molecular Biology (Clifton,... 2022Antibiotic resistance constitutes a global threat and could lead to a future pandemic. One strategy is to develop a new generation of antimicrobials. Naturally occurring...
Antibiotic resistance constitutes a global threat and could lead to a future pandemic. One strategy is to develop a new generation of antimicrobials. Naturally occurring antimicrobial peptides (AMPs) are recognized templates and some are already in clinical use. To accelerate the discovery of new antibiotics, it is useful to predict novel AMPs from the sequenced genomes of various organisms. The antimicrobial peptide database (APD) provided the first empirical peptide prediction program. It also facilitated the testing of the first machine-learning algorithms. This chapter provides an overview of machine-learning predictions of AMPs. Most of the predictors, such as AntiBP, CAMP, and iAMPpred, involve a single-label prediction of antimicrobial activity. This type of prediction has been expanded to antifungal, antiviral, antibiofilm, anti-TB, hemolytic, and anti-inflammatory peptides. The multiple functional roles of AMPs annotated in the APD also enabled multi-label predictions (iAMP-2L, MLAMP, and AMAP), which include antibacterial, antiviral, antifungal, antiparasitic, antibiofilm, anticancer, anti-HIV, antimalarial, insecticidal, antioxidant, chemotactic, spermicidal activities, and protease inhibiting activities. Also considered in predictions are peptide posttranslational modification, 3D structure, and microbial species-specific information. We compare important amino acids of AMPs implied from machine learning with the frequently occurring residues of the major classes of natural peptides. Finally, we discuss advances, limitations, and future directions of machine-learning predictions of antimicrobial peptides. Ultimately, we may assemble a pipeline of such predictions beyond antimicrobial activity to accelerate the discovery of novel AMP-based antimicrobials.
Topics: Amino Acids; Anti-Infective Agents; Antimicrobial Peptides; Machine Learning; Peptides
PubMed: 35298806
DOI: 10.1007/978-1-0716-1855-4_1 -
Theranostics 2023Recent studies indicate that microglial activation and the resulting inflammatory response could be potential targets of adjuvant therapy for ischemic stroke. Many...
Recent studies indicate that microglial activation and the resulting inflammatory response could be potential targets of adjuvant therapy for ischemic stroke. Many studies have emphasized a well-established function of Annexin-A1 (ANXA1) in the immune system, including the regulation of microglial activation. Nevertheless, few therapeutic interventions targeting ANXA1 in microglia for ischemic stroke have been conducted. In the present study, Tat-NTS, a small peptide developed to prevent ANXA1 from entering the nucleus, was utilized. We discovered the underlying mechanism that Tat-NTS peptide targets microglial ANXA1 to protect against ischemic brain injury. Preclinical studies of ischemic stroke were performed using an oxygen-glucose deprivation and reperfusion (OGD/R) cell model in vitro and the middle cerebral artery occlusion (MCAO) animal model of ischemic stroke in vivo. Confocal imaging and 3D reconstruction analyses for detecting the protein expression and subcellular localization of microglia in vivo. Co-immunoprecipitation (Co-IP), immunoblotting, ELISA, quantitative real-time PCR (qRT-PCR), Luciferase reporter assay for determining the precise molecular mechanism. Measurement on the cytotoxicity of Tat-NTS peptide for microglia was assessed by CCK-8 and LDH assay. TUNEL staining was used to detect the microglia conditioned medium-mediated neuronal apoptosis. Adeno-associated viruses (AAVs) were injected into the cerebral cortex, striatum and hippocampal CA1 region of adult male Cx3cr1-Cre mice, to further verify the neurofunctional outcome and mechanism of Tat-NTS peptide by TTC staining, the modified Neurological Severity Score (mNSS) test, the open field test (OFT), the novel object recognition task (NORT), the Morris water maze (MWM) test, the long-term potentiation (LTP) and the Transmission electron microscopy (TEM). It was observed that administration of Tat-NTS led to a shift of subcellular localization of ANXA1 in microglia from the nucleus to the cytoplasm in response to ischemic injury. Notably, this shift was accompanied by an increase in ANXA1 SUMOylation in microglia and a transformation of microglia towards an anti-inflammatory phenotype. We confirmed that Tat-NTS-induced ANXA1 SUMOylation in microglia mediated IKKα degradation via NBR1-dependent selective autophagy, then blocking the activation of the NF-κB pathway. As a result, the expression and release of the pro-inflammatory factors IL-1β and TNF-α were reduced in both in vitro and in vivo experiments. Furthermore, we found that Tat-NTS peptide's protective effect on microglia relieved ischemic neuron apoptosis. Finally, we demonstrated that Tat-NTS peptide administration, through induction of ANXA1 SUMOylation in microglia, reduced infarct volume, improved neurological function and facilitated behavioral recovery in MCAO mice. Our study provides evidence for a novel mechanism of Tat-NTS peptide in regulating microglial ANXA1 function and its substantial neuroprotective effect on neurons with ischemic injuries. These findings suggest that Tat-NTS peptides have a high potential for clinical application and may be a promising therapeutic candidate for treating cerebral ischemia.
Topics: Mice; Animals; Male; Microglia; Annexin A1; Sumoylation; Brain Ischemia; Infarction, Middle Cerebral Artery; Peptides; Ischemic Stroke; Reperfusion Injury; Neurons
PubMed: 37908731
DOI: 10.7150/thno.85390 -
Molecules (Basel, Switzerland) May 2020In recent years, the peptide drug discovery field has shown a high level of dynamism, with hundreds of academic groups working on this topic, the creation of new...
In recent years, the peptide drug discovery field has shown a high level of dynamism, with hundreds of academic groups working on this topic, the creation of new peptide-focused companies, and the consolidation of peptide business by so-called big pharma [...].
Topics: Drug Discovery; Drug Industry; Humans; Peptides
PubMed: 32414106
DOI: 10.3390/molecules25102293 -
Chemical Society Reviews May 2018Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of... (Review)
Review
Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the applications for which they can be exploited. It has recently been appreciated that nanomaterials composed of multicomponent coassembled peptides often display unique emergent properties that have the potential to dramatically expand the functional utility of peptide-based materials. This review presents recent efforts in the development of multicomponent peptide assemblies. The discussion includes multicomponent assemblies derived from short low molecular weight peptides, peptide amphiphiles, coiled coil peptides, collagen, and β-sheet peptides. The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.
Topics: Molecular Weight; Nanostructures; Peptides; Protein Conformation
PubMed: 29697126
DOI: 10.1039/c8cs00115d -
Chemical Society Reviews May 2018Self-assembly of molecules often results in new emerging properties. Even very short peptides can self-assemble into structures with a variety of physical and structural... (Review)
Review
Self-assembly of molecules often results in new emerging properties. Even very short peptides can self-assemble into structures with a variety of physical and structural characteristics. Remarkably, many peptide assemblies show high catalytic activity in model reactions reaching efficiencies comparable to those found in natural enzymes by weight. In this review, we discuss different strategies used to rationally develop self-assembled peptide catalysts with natural and unnatural backbones as well as with metal-containing cofactors.
Topics: Catalysis; Molecular Structure; Organometallic Compounds; Peptides
PubMed: 29594277
DOI: 10.1039/c8cs00080h