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Molecules (Basel, Switzerland) Nov 2023Peptide compounds play a significant role in medicinal chemistry as they can inhibit the activity of species that cause malaria. This literature review summarizes the... (Review)
Review
Peptide compounds play a significant role in medicinal chemistry as they can inhibit the activity of species that cause malaria. This literature review summarizes the isolation of antimalarial peptides, the synthesis method with the detailed structure and sequences of each peptide, and discusses the biological activity of the isolated and synthesized compounds. The synthetic routes and reactions for cyclic and linear antimalarial peptides are systematically highlighted in this review including preparing building blocks, protection and deprotection, coupling and cyclization reactions until the target compound is obtained. Based on the literature data and the results, this review's aim is to provide information to discover and synthesize more antimalarial peptide for future research.
Topics: Humans; Antimalarials; Peptides; Malaria; Cyclization; Chemistry, Pharmaceutical; Peptides, Cyclic
PubMed: 38067508
DOI: 10.3390/molecules28237778 -
Journal of the American Chemical Society Dec 2023Chemical synthesis offers robust tactics for structural alterations of peptides and proteins. It remains a labor-intensive and complex process due to the challenges in...
Chemical synthesis offers robust tactics for structural alterations of peptides and proteins. It remains a labor-intensive and complex process due to the challenges in selectively modifying diverse amino acid side chains and termini. Direct α-peptide ligation without premodification is a significant hurdle, especially when aiming to include all proteinogenic amino acids at the ligation site. We introduce Native Peptide Cyclization (NPC), a chemoselective method enabling intramolecular peptidyl ligation without the need for premodification. NPC cyclizes unprotected linear peptides through controlled, sequential C- and N-terminal activation via pH modulation. Water-based NPC simplifies peptide ligation, easing the labor-intensive nature of peptide synthesis, aiding efficient cyclic peptide preparation and enabling cost-effective macrocycle-based therapeutics.
Topics: Cyclization; Water; Peptides; Proteins; Peptides, Cyclic; Amino Acids
PubMed: 38079358
DOI: 10.1021/jacs.3c10341 -
The FEBS Journal Dec 2023Functional networks in cells are created by physical, genetic, and regulatory interactions. Mapping them and annotating their functions by available methods remains a...
Functional networks in cells are created by physical, genetic, and regulatory interactions. Mapping them and annotating their functions by available methods remains a challenge. We use affinity purification mass spectrometry (AP-MS) coupled with SLiMFinder to discern such a network involving 26S proteasome non-ATPase regulatory subunit 9 (PSMD9), a chaperone of proteasome assembly. Approximately 20% of proteins within the PSMD9 interactome carry a short linear motif (SLiM) of the type 'EXKK'. The binding of purified PSMD9 with the peptide sequence ERKK, proteins heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNPA2B1; containing ERKK), and peroxiredoxin-6 (PRDX6; containing EAKK) provided proof of principle for this motif-driven network. The EXKK motif in the peptide primarily interacts with the coiled-coil N domain of PSMD9, a unique interaction not reported for any coiled-coil domain. PSMD9 knockout (KO) HEK293 cells experience endoplasmic reticulum (ER) stress and respond by increasing the unfolded protein response (UPR) and reducing the formation of aggresomes and lipid droplets. Trans-expression of PSMD9 in the KO cells rescues lipid droplet formation. Overexpression of PSMD9 in HEK293 cells results in reduced UPR, and increased lipid droplet and aggresome formation. The outcome argues for the prominent role of PSMD9 in maintaining proteostasis. Probable mechanisms involve the binding of PSMD9 to binding immunoglobulin protein (BIP/GRP78; containing EDKK), an endoplasmic reticulum chaperone and key regulator of the UPR, and fatty acid synthase (FASN; containing ELKK), involved in fatty acid synthesis/lipid biogenesis. We propose that PSMD9 acts as a buffer in the cellular milieu by moderating the UPR and enhancing aggresome formation to reduce stress-induced proteotoxicity. Akin to waves created in ponds that perpetuate to a distance, perturbing the levels of PSMD9 would cause ripples down the networks, affecting final reactions in the pathway, one of which is altered proteostasis.
Topics: Humans; Proteasome Endopeptidase Complex; Proteostasis; HEK293 Cells; Molecular Chaperones; Unfolded Protein Response; Endoplasmic Reticulum Stress; Endoplasmic Reticulum Chaperone BiP; Carrier Proteins; Peptides
PubMed: 37665644
DOI: 10.1111/febs.16948 -
Chembiochem : a European Journal of... Jul 2023Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides...
Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides have received special attention owing to their capacity to mimic protein structures or be key components of peptide-drug conjugates. Here, we describe the development of novel synthetic strategies for two distinctive types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced for the production of interconnected β-turns, allowing two macrocyclic rings to be formed and dimerized in one pot. Also, an on-resin double stapling strategy is described for the assembly of lactam-bridged macrobicycles with stable tertiary folds.
Topics: Peptides, Cyclic; Cyclization; Peptides; Lactams; Molecular Conformation
PubMed: 37171138
DOI: 10.1002/cbic.202300229 -
International Journal of Molecular... May 2024The evolution of the translation system is a fundamental issue in the quest for the origin of life. A feasible evolutionary scenario necessitates the autonomous... (Review)
Review
The evolution of the translation system is a fundamental issue in the quest for the origin of life. A feasible evolutionary scenario necessitates the autonomous emergence of a protoribosome capable of catalyzing the synthesis of the initial peptides. The peptidyl transferase center (PTC) region in the modern ribosomal large subunit is believed to retain a vestige of such a prebiotic non-coded protoribosome, which would have self-assembled from random RNA chains, catalyzed peptide bond formation between arbitrary amino acids, and produced short peptides. Recently, three research groups experimentally demonstrated that several distinct dimeric constructs of protoribosome analogues, derived predicated on the approximate 2-fold rotational symmetry inherent in the PTC region, possess the ability to spontaneously fold, dimerize, and catalyze the formation of peptide bonds and of short peptides. These dimers are examined, aiming at retrieving information concerned with the characteristics of a prebiotic protoribosome. The analysis suggests preconditions for the laboratory re-creation of credible protoribosome analogues, including the preference of a heterodimer protoribosome, contradicting the common belief in the precedence of homodimers. Additionally, it derives a dynamic process which possibly played a role in the spontaneous production of the first bio-catalyzed peptides in the prebiotic world.
Topics: Ribosomes; Peptides; Origin of Life; Peptidyl Transferases; Protein Biosynthesis
PubMed: 38732179
DOI: 10.3390/ijms25094960 -
Nature Structural & Molecular Biology Mar 2024Hepatitis B virus (HBV), a leading cause of developing hepatocellular carcinoma affecting more than 290 million people worldwide, is an enveloped DNA virus...
Hepatitis B virus (HBV), a leading cause of developing hepatocellular carcinoma affecting more than 290 million people worldwide, is an enveloped DNA virus specifically infecting hepatocytes. Myristoylated preS1 domain of the HBV large surface protein binds to the host receptor sodium-taurocholate cotransporting polypeptide (NTCP), a hepatocellular bile acid transporter, to initiate viral entry. Here, we report the cryogenic-electron microscopy structure of the myristoylated preS1 (residues 2-48) peptide bound to human NTCP. The unexpectedly folded N-terminal half of the peptide embeds deeply into the outward-facing tunnel of NTCP, whereas the C-terminal half formed extensive contacts on the extracellular surface. Our findings reveal an unprecedented induced-fit mechanism for establishing high-affinity virus-host attachment and provide a blueprint for the rational design of anti-HBV drugs targeting virus entry.
Topics: Humans; Hepatitis B virus; Hepatocytes; Protein Binding; Virus Attachment; Peptides; Symporters; Virus Internalization
PubMed: 38233573
DOI: 10.1038/s41594-023-01191-5 -
Molecular Metabolism Oct 2023Pro-peptide precursors are processed into biologically active peptide hormones or neurotransmitters, each playing an essential role in physiology and disease. Genetic...
OBJECTIVE
Pro-peptide precursors are processed into biologically active peptide hormones or neurotransmitters, each playing an essential role in physiology and disease. Genetic loss of function of a pro-peptide precursor results in the simultaneous ablation of all biologically-active peptides within that precursor, often leading to a composite phenotype that can be difficult to align with the loss of specific peptide components. Due to this biological constraint and technical limitations, mice carrying the selective ablation of individual peptides encoded by pro-peptide precursor genes, while leaving the other peptides unaffected, have remained largely unaddressed.
METHODS
We developed and characterized a mouse model carrying the selective knockout of the TLQP-21 neuropeptide (ΔTLQP-21) encoded by the Vgf gene. To achieve this goal, we used a knowledge-based approach by mutating a codon in the Vgf sequence leading to the substitution of the C-terminal Arginine of TLQP-21, which is the pharmacophore as well as an essential cleavage site from its precursor, into Alanine (R→A).
RESULTS
We provide several independent validations of this mouse, including a novel in-gel digestion targeted mass spectrometry identification of the unnatural mutant sequence, exclusive to the mutant mouse. ΔTLQP-21 mice do not manifest gross behavioral and metabolic abnormalities and reproduce well, yet they have a unique metabolic phenotype characterized by an environmental temperature-dependent resistance to diet-induced obesity and activation of the brown adipose tissue.
CONCLUSIONS
The ΔTLQP-21 mouse line can be a valuable resource to conduct mechanistic studies on the necessary role of TLQP-21 in physiology and disease, while also serving as a platform to test the specificity of novel antibodies or immunoassays directed at TLQP-21. Our approach also has far-reaching implications by informing the development of knowledge-based genetic engineering approaches to generate selective loss of function of other peptides encoded by pro-hormones genes, leaving all other peptides within the pro-protein precursor intact and unmodified.
Topics: Animals; Mice; Diet; Homeostasis; Neuropeptides; Peptide Fragments; Peptide Hormones; Energy Metabolism
PubMed: 37482186
DOI: 10.1016/j.molmet.2023.101781 -
Peptides Nov 2023Skin aging refers to a degenerative process that can be affected and regulated by intrinsic and extrinsic factors. The mesenchymal stem cell secretome covers a...
A novel functional peptide, named EQ-9 (ESETRILLQ), identified by virtual screening from regenerative cell secretome and its potential anti-aging and restoration effects in topical applications.
Skin aging refers to a degenerative process that can be affected and regulated by intrinsic and extrinsic factors. The mesenchymal stem cell secretome covers a considerable number of regenerative molecules with anti-aging effects in a wide variety of circumstances. However, it is complex, time-consuming, and costly to identify specific compounds from thousands of natural molecules using conventional methods. With the development of computational biology and machine learning, an efficient workflow was generated to identify novel peptides with anti-aging and skin restoration potential. One of the candidate peptides was discovered and subsequently truncated to a novel peptide named EQ-9, with promising anti-aging effects for topical applications at a concentration of 10 ppm validated by experimental validation. The above-described paradigm is expected to be further applied to the virtual screening of novel peptide molecules targeting specific biological functions from a wide variety of natural resources.
Topics: Regenerative Medicine; Secretome; Mesenchymal Stem Cells; Peptides
PubMed: 37579838
DOI: 10.1016/j.peptides.2023.171078 -
Journal of the International Society of... Dec 2023Accumulation of body fat and dyslipidemia are associated with the development of obesity and cardiometabolic diseases. Moreover, the degree to which lipids can be... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Accumulation of body fat and dyslipidemia are associated with the development of obesity and cardiometabolic diseases. Moreover, the degree to which lipids can be metabolized has been cited as a determinant of cardiometabolic health and prolonged endurance capacity. In the backdrop of increasing obesity and cardiometabolic diseases, lipid metabolism and its modulation by physical activity, dietary adjustments, and supplementation play a significant role in maintaining health and endurance. Food-derived oligopeptides, such as rice and soybean peptides, have been shown to directly regulate abnormal lipid metabolism or promote hypolipidemia and fat oxidation in cell culture models, animal models, and human studies. However, whether supplementation with oligopeptides derived from multiple food sources can promote lipid degradation and fat oxidation in athletes remains unclear. Therefore, in a randomized controlled crossover trial, we investigated the impact of food-derived oligopeptide supplementation before and during exercise on lipid metabolism in young male cyclists.
METHODS
Sixteen young male cyclists (age: 17.0 ± 1.0 years; height: 178.4 ± 6.9 cm; body mass: 68.7 ± 12.7 kg, body mass index: 21.5 ± 3.4 kg/m; maximum oxygen uptake: 56.3 ± 5.8 mL/min/kg) participated in this randomized controlled crossover trial. Each participant drank two beverages, one containing a blend of three food-derived oligopeptides (treatment, 0.5 g/kg body weight in total) and the other without (control), with a 2-week washout period between two experiments. The cyclists completed a one-day pattern protocol that consisted of intraday fasting, 30 min of sitting still, 85 min of prolonged exercise plus a 5-min sprint (PE), a short recovery period of 60 min, a 20-min time trial (TT), and recovery till next morning. Blood samples were collected for biochemical analyses of serum lipids and other biomarkers. We analyzed plasma triglyceride species (TGs), free amino acids (FAAs), and tricarboxylic acid (TCA) cycle intermediates using omics methods. In addition, exhaled gas was collected to assess the fat oxidation rate.
RESULTS
Five of 20 plasma FAAs were elevated pre-exercise (pre-Ex) only 20 min after oligopeptide ingestion, and most FAAs were markedly increased post PE and TT. Serum levels of TG and non-esterified fatty acids were lower in the experimental condition than in the control condition at the post PE and TT assessments, respectively. Further, the omics analysis of plasma TGs for the experimental condition demonstrated that most TGs were lower post PE and at the next fasting when compared with control levels. Simultaneously, the fat oxidation rate began to increase only 20 min after ingestion and during the preceding 85 min of PE. Levels of TCA cycle intermediates did not differ between the conditions.
CONCLUSIONS
The study noted that continuous ingestion of food-derived oligopeptides accelerated total body triglyceride breakdown, non-esterified fatty acid uptake, and fat oxidation during both sedentary and exercise states. Elevated circulating and intracellular FAA flux may modulate the selection of substrates for metabolic pathways in conjunction with the release of neuroendocrinological factors that slow down carbohydrate metabolism via acetyl coenzyme A feedback inhibition. This may increase the availability of fatty acids for energy production, with FAAs supplying more substrates for the TCA cycle. The findings of this study provide novel insight into strategies for promoting lipid metabolism in populations with dyslipidemia-related metabolic disorders such as obesity and for improving physiological functioning during endurance training. However, the absence of a non-exercising control group and verification of long-term supplementation effects was a limitation. Future studies will emphasize the impacts of whole protein supplementation as a control and of combined food-derived peptides or oligopeptides with probiotics and healthy food components on lipid metabolism in individuals who exercise.
Topics: Animals; Humans; Male; Adolescent; Lipid Metabolism; Cross-Over Studies; Oxygen Consumption; Oxygen; Oligopeptides; Amino Acids; Cardiovascular Diseases; Dietary Supplements; Lipids
PubMed: 37674290
DOI: 10.1080/15502783.2023.2254741 -
European Journal of Pharmacology Oct 2023Beta arrestins had been known as intracellular adaptors that uncouple and inactivate the G protein-coupled receptors that they interact with. Their roles as signal... (Review)
Review
BACKGROUND
Beta arrestins had been known as intracellular adaptors that uncouple and inactivate the G protein-coupled receptors that they interact with. Their roles as signal initiators for some receptors have recently been recognized.
SCOPE OF REVIEW
In this review, we focused on their role in mediating metabolic modulation primarily in relation to insulin signaling. Commenced by the upstream receptor, they seem to act like intracellular hubs that divert the metabolic profile of the cell. The amount of metabolic substrates in circulation and their usage/deposition by tissues are controlled by the contribution of all systems in the organism. This control is enabled by the release of hormones such as insulin, glucagon and glucagon-like peptide-1. Intriguingly, some ligands -either agonists or antagonists-of different classes of receptors have preferential properties mediated by β arrestins. This is not surprizing considering that substrate supply and usage should parallel physiological function such as hormone release or muscle contraction.
MAJOR CONCLUSIONS
Available data indicate that β arrestins conduct the regulatory role in insulin secretion and action. They may be good candidates to target when the upstream signal demands the function that may compromise the cell. An example is carvedilol that is protective by preventing the stimulatory effects of excessive catecholamines, stimulates mitochondrial function and has preferential clinical outcomes in metabolic disorders.
Topics: beta-Arrestins; Insulin Secretion; Arrestins; Signal Transduction; Insulin
PubMed: 37541367
DOI: 10.1016/j.ejphar.2023.175952