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Molecules (Basel, Switzerland) Dec 2023Epimerisation is basically a chemical conversion that includes the transformation of an epimer into another epimer or its chiral partner. Epimerisation of amino acid is... (Review)
Review
Epimerisation is basically a chemical conversion that includes the transformation of an epimer into another epimer or its chiral partner. Epimerisation of amino acid is a side reaction that sometimes happens during peptide synthesis. It became the most avoided reaction because the process affects the overall conformation of the molecule, eventually even altering the bioactivity of the peptide. Epimerised products have a high similarity of physical characteristics, thus making it difficult for them to be purified. In regards to amino acids, epimerisation is very important in keeping the chirality of the assembled amino acids unchanged during the peptide synthesis and obtaining the desirable product without any problematic purification. In this review, we report several factors that induce epimerisation during peptide synthesis, including how to characterise and affect the bioactivities. To avoid undesirable epimerisation, we also describe several methods of suppressing the process.
Topics: Peptides; Amino Acids
PubMed: 38138507
DOI: 10.3390/molecules28248017 -
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 -
Nature Feb 2024Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease....
Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease. De novo protein design can now generate binders with high affinity and specificity to structured proteins. However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar-affinity binders can be generated to helical peptide targets by either refining designs generated with other methods, or completely de novo starting from random noise distributions without any subsequent experimental optimization. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimize by partial diffusion both natural and designed proteins, should be broadly useful.
Topics: Biosensing Techniques; Computer-Aided Design; Deep Learning; Diffusion; Glucagon; Luminescent Measurements; Mass Spectrometry; Parathyroid Hormone; Peptides; Protein Structure, Secondary; Proteins; Substrate Specificity; Models, Molecular
PubMed: 38109936
DOI: 10.1038/s41586-023-06953-1 -
ChemMedChem Sep 2023Supramolecular assemblies made by the self-assembly of peptides are finding an increasing number of applications in various fields. While the early exploration of... (Review)
Review
Supramolecular assemblies made by the self-assembly of peptides are finding an increasing number of applications in various fields. While the early exploration of peptide assemblies centered on tissue engineering or regenerative medicine, the recent development has shown that peptide assemblies can act as supramolecular medicine for cancer therapy. This review covers the progress of applying peptide assemblies for cancer therapy, with the emphasis on the works appeared over the last five years. We start with the introduction of a few seminal works on peptide assemblies, then discuss the combination of peptide assemblies with anticancer drugs. Next, we highlight the use of enzyme-controlled transformation or shapeshifting of peptide assemblies for inhibiting cancer cells and tumors. After that, we provide the outlook for this exciting field that promises new kind of therapeutics for cancer therapy.
Topics: Humans; Peptides; Tissue Engineering; Antineoplastic Agents; Neoplasms
PubMed: 37380607
DOI: 10.1002/cmdc.202300258 -
Frontiers in Immunology 2023Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Due to the lack of specific therapeutic targets, treatment options are limited, and... (Review)
Review
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Due to the lack of specific therapeutic targets, treatment options are limited, and the recurrence and metastasis rate is high, the overall survival of patients is poor. However, with the discovery of some new targets and the corresponding immune regulation after targeting these targets, TNBC has a new hope in treatment. The peptide has a simple structure, strong binding affinity, and high stability, and has great potential in targeted therapy and immune regulation against TNBC. This review will discuss how single peptides and peptide combinations target triple-negative breast cancer to exert immunomodulatory effects. Among them, single peptides target specific receptors on TNBC cells, act as decoys to target key ligands in the regulatory pathway, and target TME-related cells. The combinations of peptides work in the form of cancer vaccines, engineered exosomes, microRNAs and other immune-related molecular pathways, immune checkpoint inhibitors, chimeric antigen receptor T cells, and drug-peptide conjugates. This article is mainly dedicated to exploring new treatment methods for TNBC to improve the curative effect and prolong the survival time of patients.
Topics: Humans; Triple Negative Breast Neoplasms; MicroRNAs; Cancer Vaccines; Erythrocytes, Abnormal; Peptides
PubMed: 37691919
DOI: 10.3389/fimmu.2023.1255820 -
International Journal of Molecular... Aug 2023Peptide-based strategies have received an enormous amount of attention because of their specificity and applicability. Their specificity and tumor-targeting ability are... (Review)
Review
Peptide-based strategies have received an enormous amount of attention because of their specificity and applicability. Their specificity and tumor-targeting ability are applied to diagnosis and treatment for cancer patients. In this review, we will summarize recent advancements and future perspectives on peptide-based strategies for cancer treatment. The literature search was conducted to identify relevant articles for peptide-based strategies for cancer treatment. It was performed using PubMed for articles in English until June 2023. Information on clinical trials was also obtained from ClinicalTrial.gov. Given that peptide-based strategies have several advantages such as targeted delivery to the diseased area, personalized designs, relatively small sizes, and simple production process, bioactive peptides having anti-cancer activities (anti-cancer peptides or ACPs) have been tested in pre-clinical settings and clinical trials. The capability of peptides for tumor targeting is essentially useful for peptide-drug conjugates (PDCs), diagnosis, and image-guided surgery. Immunomodulation with peptide vaccines has been extensively tested in clinical trials. Despite such advantages, FDA-approved peptide agents for solid cancer are still limited. This review will provide a detailed overview of current approaches, design strategies, routes of administration, and new technological advancements. We will highlight the success and limitations of peptide-based therapies for cancer treatment.
Topics: Humans; Neoplasms; Peptides; Immunomodulation; PubMed; Surgery, Computer-Assisted
PubMed: 37629112
DOI: 10.3390/ijms241612931 -
Advances in Colloid and Interface... Aug 2023The use of small-angle scattering (SAS) in the study of the self-assembly of peptides and peptide conjugates (lipopeptides, polymer-peptide conjugates and others) is... (Review)
Review
The use of small-angle scattering (SAS) in the study of the self-assembly of peptides and peptide conjugates (lipopeptides, polymer-peptide conjugates and others) is reviewed, highlighting selected research that illustrates different methods and analysis techniques. Both small-angle x-ray scattering (SAXS) and small-angle neutron scattering (SANS) are considered along with examples that exploit their unique capabilities. For SAXS, this includes the ability to perform rapid measurements enabling high throughput or fast kinetic studies and measurements under dilute conditions. For SANS, contrast variation using HO/DO mixtures enables the study of peptides interacting with lipids and TR-SANS (time-resolved SANS) studies of exchange kinetics and/or peptide-induced structural changes. Examples are provided of studies measuring form factors of different self-assembled structures (micelles, fibrils, nanotapes, nanotubes etc) as well as structure factors from ordered phases (lyotropic mesophases), peptide gels and hybrid materials such as membranes formed by mixing peptides with polysaccharides or peptide/liposome mixtures. SAXS/WAXS (WAXS: wide-angle x-ray scattering) on peptides and peptide hybrids is also discussed, and the review concludes with a perspective on potential future directions for research in the field.
Topics: Scattering, Small Angle; Kinetics; X-Ray Diffraction; Peptides; Nanostructures
PubMed: 37473606
DOI: 10.1016/j.cis.2023.102959 -
Bioorganic & Medicinal Chemistry Jul 2023Traumatic brain injury (TBI) is a leading cause of disability in adults, caused by a physical insult damaging the brain. Growth factor-based therapies have the potential... (Review)
Review
Traumatic brain injury (TBI) is a leading cause of disability in adults, caused by a physical insult damaging the brain. Growth factor-based therapies have the potential to reduce the effects of secondary injury and improve outcomes by providing neuroprotection against glutamate excitotoxicity, oxidative damage, hypoxia, and ischemia, as well as promoting neurite outgrowth and the formation of new blood vessels. Despite promising evidence in preclinical studies, few neurotrophic factors have been tested in clinical trials for TBI. Translation to the clinic is not trivial and is limited by the short in vivo half-life of the protein, the inability to cross the blood-brain barrier and human delivery systems. Synthetic peptide mimetics have the potential to be used in place of recombinant growth factors, activating the same downstream signalling pathways, with a decrease in size and more favourable pharmacokinetic properties. In this review, we will discuss growth factors with the potential to modulate damage caused by secondary injury mechanisms following a traumatic brain injury that have been trialled in other indications including spinal cord injury, stroke and neurodegenerative diseases. Peptide mimetics of nerve growth factor (NGF), hepatocyte growth factor (HGF), glial cell line-derived growth factor (GDNF), brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) will be highlighted, most of which have not yet been tested in preclinical or clinical models of TBI.
Topics: Humans; Peptides; Brain Injuries, Traumatic; Brain; Neuronal Outgrowth
PubMed: 37331175
DOI: 10.1016/j.bmc.2023.117368 -
International Journal of Molecular... Jun 2023Minimalistic peptide- and metabolite-based supramolecular hydrogels have great potential relative to traditional polymeric hydrogels in various biomedical and... (Review)
Review
Minimalistic peptide- and metabolite-based supramolecular hydrogels have great potential relative to traditional polymeric hydrogels in various biomedical and technological applications. Advantages such as remarkable biodegradability, high water content, favorable mechanical properties, biocompatibility, self-healing, synthetic feasibility, low cost, easy design, biological function, remarkable injectability, and multi-responsiveness to external stimuli make supramolecular hydrogels promising candidates for drug delivery, tissue engineering, tissue regeneration, and wound healing. Non-covalent interactions such as hydrogen bonding, hydrophobic interactions, electrostatic interactions, and π-π stacking interactions play key roles in the formation of peptide- and metabolite-containing low-molecular-weight hydrogels. Peptide- and metabolite-based hydrogels display shear-thinning and immediate recovery behavior due to the involvement of weak non-covalent interactions, making them supreme models for the delivery of drug molecules. In the areas of regenerative medicine, tissue engineering, pre-clinical evaluation, and numerous other biomedical applications, peptide- and metabolite-based hydrogelators with rationally designed architectures have intriguing uses. In this review, we summarize the recent advancements in the field of peptide- and metabolite-based hydrogels, including their modifications using a minimalistic building-blocks approach for various applications.
Topics: Hydrogels; Peptides; Regenerative Medicine; Tissue Engineering; Drug Delivery Systems
PubMed: 37373477
DOI: 10.3390/ijms241210330 -
Advanced Science (Weinheim,... Sep 2023Antimicrobial peptides (AMPs) are essential elements of thehost defense system. Characterized by heterogenous structures and broad-spectrumaction, they are promising... (Review)
Review
Antimicrobial peptides (AMPs) are essential elements of thehost defense system. Characterized by heterogenous structures and broad-spectrumaction, they are promising candidates for combating multidrug resistance. Thecombined use of AMPs with other antimicrobial agents provides a new arsenal ofdrugs with synergistic action, thereby overcoming the drawback of monotherapiesduring infections. AMPs kill microbes via pore formation, thus inhibitingintracellular functions. This mechanism of action by AMPs is an advantage overantibiotics as it hinders the development of drug resistance. The synergisticeffect of AMPs will allow the repurposing of conventional antimicrobials andenhance their clinical outcomes, reduce toxicity, and, most significantly,prevent the development of resistance. In this review, various synergies ofAMPs with antimicrobials and miscellaneous agents are discussed. The effect ofstructural diversity and chemical modification on AMP properties is firstaddressed and then different combinations that can lead to synergistic action,whether this combination is between AMPs and antimicrobials, or AMPs andmiscellaneous compounds, are attended. This review can serve as guidance whenredesigning and repurposing the use of AMPs in combination with other antimicrobialagents for enhanced clinical outcomes.
Topics: Humans; Anti-Bacterial Agents; Antimicrobial Peptides; Antimicrobial Cationic Peptides; Anti-Infective Agents; Communicable Diseases
PubMed: 37407512
DOI: 10.1002/advs.202300472