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Proceedings of the National Academy of... Jun 2019Hydrogels that are self-assembled by peptides have attracted great interest for biomedical applications. However, the link between chemical structures of peptides and...
Hydrogels that are self-assembled by peptides have attracted great interest for biomedical applications. However, the link between chemical structures of peptides and their corresponding hydrogel properties is still unclear. Here, we showed a combinational approach to generate a structurally diverse hydrogel library with more than 2,000 peptides and evaluated their corresponding properties. We used a quantitative structure-property relationship to calculate their chemical features reflecting the topological and physicochemical properties, and applied machine learning to predict the self-assembly behavior. We observed that the stiffness of hydrogels is correlated with the diameter and cross-linking degree of the nanofiber. Importantly, we demonstrated that the hydrogels support cell proliferation in culture, suggesting the biocompatibility of the hydrogel. The combinatorial hydrogel library and the machine learning approach we developed linked the chemical structures with their self-assembly behavior and can accelerate the design of novel peptide structures for biomedical use.
Topics: Biocompatible Materials; Cell Proliferation; Dipeptides; Humans; Hydrogels; Machine Learning; Nanofibers
PubMed: 31110004
DOI: 10.1073/pnas.1903376116 -
Bioconjugate Chemistry Aug 2023Peptide nucleic acids and their conjugates to peptides can self-assemble and generate complex architectures. In this work, we explored the self-assembly of PNA dimers...
Peptide nucleic acids and their conjugates to peptides can self-assemble and generate complex architectures. In this work, we explored the self-assembly of PNA dimers conjugated to the dipeptide WW. Our studies suggest that the indole ring of tryptophan promotes aggregation of the conjugates. The onset of fluorescence is observed upon self-assembly. The structure of self-assembled WWgc is concentration-dependent, being spherical at low concentrations and fibrous at high concentrations. As suggested by molecular modeling studies, fibers are stabilized by stacking interactions between tryptophans and Watson-Crick hydrogen bonds between nucleobases.
Topics: Tryptophan; Peptide Nucleic Acids; Dipeptides; Peptides; Models, Molecular
PubMed: 37486977
DOI: 10.1021/acs.bioconjchem.3c00200 -
Molecules (Basel, Switzerland) Jun 2021Cyclodipeptides (CDPs) or 2,5-diketopiperazines (DKPs) can exert a variety of biological activities and display pronounced resistance against enzymatic hydrolysis as... (Review)
Review
Cyclodipeptides (CDPs) or 2,5-diketopiperazines (DKPs) can exert a variety of biological activities and display pronounced resistance against enzymatic hydrolysis as well as a propensity towards self-assembly into gels, relative to the linear-dipeptide counterparts. They have attracted great interest in a variety of fields spanning from functional materials to drug discovery. This concise review will analyze the latest advancements in their synthesis, self-assembly into gels, and their more innovative applications.
Topics: Diketopiperazines; Dipeptides; Gels; Green Chemistry Technology; Microwaves; Molecular Structure; Peptides, Cyclic
PubMed: 34204905
DOI: 10.3390/molecules26113376 -
Proceedings of the National Academy of... Oct 2022Amide bond formation, the essential condensation reaction underlying peptide synthesis, is hindered in aqueous systems by the thermodynamic constraints associated with...
Amide bond formation, the essential condensation reaction underlying peptide synthesis, is hindered in aqueous systems by the thermodynamic constraints associated with dehydration. This represents a key difficulty for the widely held view that prebiotic chemical evolution leading to the formation of the first biomolecules occurred in an oceanic environment. Recent evidence for the acceleration of chemical reactions at droplet interfaces led us to explore aqueous amino acid droplet chemistry. We report the formation of dipeptide isomer ions from free glycine or L-alanine at the air-water interface of aqueous microdroplets emanating from a single spray source (with or without applied potential) during their flight toward the inlet of a mass spectrometer. The proposed isomeric dipeptide ion is an oxazolidinone that takes fully covalent and ion-neutral complex forms. This structure is consistent with observed fragmentation patterns and its conversion to authentic dipeptide ions upon gentle collisions and for its formation from authentic dipeptides at ultra-low concentrations. It also rationalizes the results of droplet fusion experiments that show that the dipeptide isomer facilitates additional amide bond formation events, yielding authentic tri- through hexapeptides. We propose that the interface of aqueous microdroplets serves as a drying surface that shifts the equilibrium between free amino acids in favor of dehydration via stabilization of the dipeptide isomers. These findings offer a possible solution to the water paradox of biopolymer synthesis in prebiotic chemistry.
Topics: Alanine; Amides; Amino Acids; Biopolymers; Dehydration; Dipeptides; Glycine; Humans; Oxazolidinones; Peptides; Water
PubMed: 36191178
DOI: 10.1073/pnas.2212642119 -
Journal of Agricultural and Food... Apr 2022Biotic stresses (fungi, bacteria, insects, weeds, etc.) are some of the most important causes of the decrease in the quality and quantity of crops that could become an...
Biotic stresses (fungi, bacteria, insects, weeds, etc.) are some of the most important causes of the decrease in the quality and quantity of crops that could become an emergency due to a noteworthy increase in the world population. Thus, to overcome these problems, massive use of chemical pesticides has been carried out with heavy consequences for environmental pollution and food safety. An eco-friendly alternative can be using natural compound-based biopesticides with high efficacy and selectivity. Some bacterial lipodepsipeptides (tolaasins I, II, A, D, and E and WLIP together with hexacetyl- and tetrahydro-tolaasin I and WLIP methyl ester) and cyclic dipeptides (cyclo(l-Pro-l-Tyr), cyclo(d-Pro-l-Tyr), cyclo(l-Pro-l-Val), and cyclo(l-Pro-l-Leu)) were assayed against several pathogenic bacteria and fungi of important agrarian plants. Lipodepsipeptides showed strong growth inhibition of all microorganisms tested in the range of 0.1-0.8 μg/mL, while cyclodipeptides, despite preserving this ability, showed a noteworthily reduced antimicrobial activity being active only in the range of 15-900 μg/mL. Among the lipodepsipeptides and cyclic dipeptides assayed, tolaasin d and cyclo(l-Pro-l-Tyr) (also named maculosin-1) appeared to be the most toxic compounds. Some structure-activity relationships of lipodepsipeptides were also discussed along with their practical application as biopesticides in agriculture.
Topics: Bacteria; Biological Control Agents; Dipeptides; Fungi; Microbial Sensitivity Tests; Peptides, Cyclic; Plants
PubMed: 35395154
DOI: 10.1021/acs.jafc.1c08139 -
Cellular Physiology and Biochemistry :... 2018The aim of this study was to investigate the transport properties and utilization of methionyl-methionine dipeptide (Met-Met) in β-casein (β-CN) synthesis in bovine...
BACKGROUND/AIMS
The aim of this study was to investigate the transport properties and utilization of methionyl-methionine dipeptide (Met-Met) in β-casein (β-CN) synthesis in bovine mammary epithelial cells (BMECs).
METHODS
The transport properties were studied for the effects of time, pH, concentration, temperature and inhibitors using Met-Met-FITC in BMECs. BMECs were treated with different concentrations of Met-Met (0, 20, 40, 80, 120 and 160 µg/ml). In several experiments, the cells were treated with Janus kinase 2 (JAK2) inhibitor (tyrphostin AG-490, 50 µM) and mammalian target of rapamycin (mTOR) inhibitor (rapamycin, 100 ng/ml).
RESULTS
The uptake of Met-Met-FITC by BMECs was rapid during the first fifteen minutes and became saturated after 15 minutes. The transport of Met-Met-FITC in BMECs exhibited a Michaelis constant of 52.4 µM and maximum transport velocity of 14.8 pmol/min/mg protein. The uptake of Met-Met-FITC in BMECs was pH-dependent, peaked at pH 6.5 and was significantly inhibited by other peptides, including Met-Lys, Lys-Lys, Gly-Met, Gly-Leu and Met-Leu. Knocking down the peptide transporter 2 (PepT2) with small interference RNA markedly decreased Met-Met-FITC uptake. Met-Met concentration-dependently increased the PepT2 expression and β-CN synthesis in BMECs with an optimal concentration of 80 µg/ml. At 80 µg/ml, Met-Met also enhanced the cell viability and cyclin D1 expression and promoted cell cycle transition from G1 phase to S phase. In addition, 80 µg/ml Met-Met increased the mRNA abundance of JAK2 and signal transducer and activator of transcription 5 (STAT5) and enhanced the phosphorylation of JAK2, STAT5, mTOR, p70 ribosomal S6 kinase 1 and eukaryotic initiation factor 4E binding protein 1. The inhibition of JAK2 and mTOR significantly decreased Met-Met-induced increase in cell viability and β-CN synthesis in BMECs.
CONCLUSION
Our data elucidated the properties of peptide transporter and its effect on β-CN synthesis in BMECs. Met-Met, taken up by PepT2, enhances cell proliferation and promotes β-CN synthesis by activating JAK2-STAT5 and mTOR signaling pathways in BMECs.
Topics: Animals; Caseins; Cattle; Cell Survival; Cells, Cultured; Cyclin D1; Dipeptides; Epithelial Cells; Female; Fluorescein-5-isothiocyanate; Hydrogen-Ion Concentration; Janus Kinase 2; Mammary Glands, Animal; RNA Interference; RNA, Small Interfering; STAT5 Transcription Factor; Signal Transduction; Symporters; TOR Serine-Threonine Kinases; Up-Regulation
PubMed: 30157477
DOI: 10.1159/000492987 -
Molecules (Basel, Switzerland) Nov 2012Pseudopeptides containing the phosphinate moiety (-P(O)(OH)CH(2)-) have been studied extensively, mainly as transition state analogue inhibitors of metalloproteases. The... (Review)
Review
Pseudopeptides containing the phosphinate moiety (-P(O)(OH)CH(2)-) have been studied extensively, mainly as transition state analogue inhibitors of metalloproteases. The key synthetic aspect of their chemistry is construction of phosphinic dipeptide derivatives bearing appropriate side-chain substituents. Typically, this synthesis involves a multistep preparation of two individual building blocks, which are combined in the final step. As this methodology does not allow simple variation of the side-chain structure, many efforts have been dedicated to the development of alternative approaches. Recent achievements in this field are summarized in this review. Improved methods for the formation of the phosphinic peptide backbone, including stereoselective and multicomponent reactions, are presented. Parallel modifications leading to the structurally diversified substituents are also described. Finally, selected examples of the biomedical applications of the title compounds are given.
Topics: Acrylates; Alkylation; Animals; Dipeptides; Humans; Hydrolysis; Phosphinic Acids; Solid-Phase Synthesis Techniques
PubMed: 23154272
DOI: 10.3390/molecules171113530 -
Physiological Reports Oct 2023We evaluated whether anserine, a methylated analog of the dipeptide carnosine, is present in the cardiac and skeletal muscles of humans and whether the CARNMT1 gene,...
We evaluated whether anserine, a methylated analog of the dipeptide carnosine, is present in the cardiac and skeletal muscles of humans and whether the CARNMT1 gene, which encodes the anserine synthesizing enzyme carnosine-N-methyltransferase, is expressed in human skeletal muscle. We found that anserine is present at low concentrations (low micromolar range) in both cardiac and skeletal muscles, and that anserine content in skeletal muscle is ~15 times higher than in cardiac muscle (cardiac muscle: 10.1 ± 13.4 μmol·kg of dry muscle, n = 12; skeletal muscle: 158.1 ± 68.5 μmol·kg of dry muscle, n = 11, p < 0.0001). Anserine content in the heart was highly variable between individuals, ranging from 1.4 to 45.4 μmol·kg of dry muscle, but anserine content was not associated with sex, age, or body mass. We also showed that CARNMT1 gene is poorly expressed in skeletal muscle (n = 10). This is the first study to demonstrate that anserine is present in the ventricle of the human heart. The presence of anserine in human heart and the confirmation of its expression in human skeletal muscle open new avenues of investigation on the specific and differential physiological functions of histidine dipeptides in striated muscles.
Topics: Humans; Anserine; Carnosine; Muscle, Skeletal; Dipeptides; Myocardium
PubMed: 37771070
DOI: 10.14814/phy2.15833 -
Nutrients Sep 2023Non-alcoholic fatty liver disease (NAFLD) manifests as a persistent liver ailment marked by the excessive buildup of lipids within the hepatic organ accompanied by...
Non-alcoholic fatty liver disease (NAFLD) manifests as a persistent liver ailment marked by the excessive buildup of lipids within the hepatic organ accompanied by inflammatory responses and oxidative stress. Alanyl-glutamine (AG), a dipeptide comprising alanine and glutamine, is commonly employed as a nutritional supplement in clinical settings. This research aims to evaluate the impact of AG on NAFLD triggered by a high-fat diet (HFD), while concurrently delving into the potential mechanisms underlying its effects. The results presented herein demonstrate a notable reduction in the elevated body weight, liver mass, and liver index induced by a HFD upon AG administration. These alterations coincide with the amelioration of liver injury and the attenuation of hepatic histological advancement. Furthermore, AG treatment manifests a discernible diminution in oil-red-O-stained regions and triglyceride (TG) levels within the liver. Noteworthy alterations encompass lowered plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) concentrations, coupled with elevated high-density lipoprotein cholesterol (HDLC) concentrations. The mitigation of hepatic lipid accumulation resultant from AG administration is aligned with the downregulation of ACC1, SCD1, PPAR-γ, and CD36 expression, in conjunction with the upregulation of FXR and SHP expression. Concomitantly, AG administration leads to a reduction in the accumulation of F4/80-positive macrophages within the liver, likely attributable to the downregulated expression of MCP-1. Furthermore, AG treatment yields a decline in hepatic MDA levels and a concurrent increase in the activities of SOD and GPX. A pivotal observation underscores the effect of AG in rectifying the imbalance of gut microbiota in HFD-fed mice. Consequently, this study sheds light on the protective attributes of AG against HFD-induced NAFLD through the modulation of gut microbiota composition.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Diet, High-Fat; Gastrointestinal Microbiome; Dysbiosis; Liver; Dipeptides; Cholesterol; Mice, Inbred C57BL
PubMed: 37764772
DOI: 10.3390/nu15183988 -
Nature Communications Nov 2022Stability of eukaryotic mRNAs is associated with their codon, amino acid, and GC content. Yet, coding sequence motifs that predictably alter mRNA stability in human...
Stability of eukaryotic mRNAs is associated with their codon, amino acid, and GC content. Yet, coding sequence motifs that predictably alter mRNA stability in human cells remain poorly defined. Here, we develop a massively parallel assay to measure mRNA effects of thousands of synthetic and endogenous coding sequence motifs in human cells. We identify several families of simple dipeptide repeats whose translation triggers mRNA destabilization. Rather than individual amino acids, specific combinations of bulky and positively charged amino acids are critical for the destabilizing effects of dipeptide repeats. Remarkably, dipeptide sequences that form extended β strands in silico and in vitro slowdown ribosomes and reduce mRNA levels in vivo. The resulting nascent peptide code underlies the mRNA effects of hundreds of endogenous peptide sequences in the human proteome. Our work suggests an intrinsic role for the ribosome as a selectivity filter against the synthesis of bulky and aggregation-prone peptides.
Topics: Humans; Protein Biosynthesis; RNA Stability; RNA, Messenger; Peptides; Amino Acids; Dipeptides
PubMed: 36369503
DOI: 10.1038/s41467-022-34664-0