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Microwaves have been successfully employed in the Lewis acid titanium tetrachloride-assisted synthesis of peptide systems. Dipeptide systems with their amino function differently protected with urethane protecting groups have been synthesized in short periods of time and with high yields. The formation of the peptide bond between the two reacting amino acids was achieved in pyridine by using titanium tetrachloride as a condensing agent and heating the reaction mixture with a microwave reactor. The reaction conditions are compatible with amino acids featuring various side chains and different protecting groups on both the amino function and side chains. Additionally, the substrates retain their chiral integrity after reaction.

Elucidating unknown structures of proteins, such as metastable states, is critical in designing therapeutic agents. Protein structure exploration has been performed using advanced computational methods, especially molecular dynamics and Markov chain Monte Carlo simulations, which require untenably long calculation times and prior structural knowledge. Here, we developed an innovative method for protein structure determination called never give up protein exploration (NPEX) with deep reinforcement learning. The NPEX method leverages the soft actor-critic algorithm and the intrinsic reward system, effectively adding a bias potential without the need for prior knowledge. To demonstrate the method's effectiveness, we applied it to four models: a double well, a triple well, the alanine dipeptide, and the tryptophan cage. Compared with Markov chain Monte Carlo simulations, NPEX had markedly greater sampling efficiency. The significantly enhanced computational efficiency and lack of prior domain knowledge requirements of the NPEX method will revolutionize protein structure exploration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A new alkaloid named aspergilalkaloid A ( 1 ) with pyridoindole hydroxymethyl piperazine dione structure along with six known compounds 2-7 were isolated from deep-sea derived fungus Aspergillus sp. HDN20-1401. The structure including absolute configuration was elucidated by extensive NMR analyses, HRESIMS, ECD calculation, and theoretical NMR calculation with DP4+ analysis. All isolated compounds were tested for antimicrobial and anticancer activity. Aspergilalkaloid A ( 1 ) showed inhibitive activity against Bacillus cereus with MIC value of 12.5  μ M and weak activity against MRCNS.

Despite the remarkable developments of the Ugi reaction and its variants, the use of ammonia in the Ugi reaction has long been recognized as impractical and unsuccessful. Indeed, the ammonia-Ugi reaction often requires harsh reaction conditions, such as heating and microwave irradiation, and competes with the Passerini reaction, thereby resulting in low yields. This study describes a robust and practical ammonia-Ugi reaction protocol. Using originally prepared ammonium carboxylates in trifluoroethanol, the ammonia-Ugi reaction proceeded at room temperature in high yields and showed a broad substrate scope, thus synthesizing a variety of α,α-disubstituted amino acid derivatives, including unnatural dipeptides. The reaction required no condensing agents and proceeded without racemization of the chiral stereocenter of α-amino acids. Furthermore, using this protocol, we quickly synthesized a novel dipeptide, D-Leu-Aic-NH-CH 2 Ph( p -F), which exhibited a potent inhibitory activity against α-chymotrypsin with a K i value of 0.091 μM.

A dipeptide-based bifunctional material immobilized with Ti 4+ (denoted as APE-MBA-VPA-Ti 4+ ) was developed using precipitation polymerization. This polymer combines hydrophilic interaction liquid chromatography (HILIC) and immobilized metal affinity chromatography (IMAC) enrichment strategies, allowing for the individual and simultaneous enrichment of glycopeptides and phosphopeptides. It demonstrated high sensitivity (0.1 fmol μL -1 for glycopeptides, 0.005 fmol μL -1 for phosphopeptides), strong selectivity (molar ratio HRP: BSA = 1:1000, β-casein: BSA = 1:2500), consistent reusability (10 cycles) and satisfactory recovery rate (93.5 ± 1.8 % for glycopeptides, 91.6 ± 0.6 % for phosphopeptides) in the individual enrichment. Utilizing nano LC-MS/MS technology, the serum of liver cancer patients was analyzed after enrichment individually, resulting in the successful capture of 333 glycopeptides covering 262 glycosylation sites, corresponding to 131 glycoproteins, as well as 67 phosphopeptides covering 57 phosphorylation sites, related to 48 phosphoproteins. In comparison, the serum of normal healthy individuals yielded a total of 283 glycopeptides covering 244 glycosylation sites corresponding to 126 glycoproteins, as well as 66 phosphopeptides covering 56 phosphorylation sites related to 37 phosphoproteins. Label-free quantification identified 10 differentially expressed glycoproteins and 8 differentially expressed phosphoproteins in the serum of liver cancer patients. Among them, glycoproteins (HP, BCHE, AGT, C3, and PROC) and phosphoproteins (ZYX, GOLM1, GP1BB, CLU, and TNXB) showed upregulation and displayed potential as biomarkers for liver cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chromatographic behavior of new chiral stationary phases (CSPs) Chiral-T and Chiral-V with teicoplanin and vancomycin antibiotics grafted onto superficially porous silica particles was studied in relation to dipeptide (DP) stereoisomers. The unbuffered water-methanol solutions were used as mobile phases (MPs). The effects of physical properties and molecular structure of analytes and selectors on retention and separation of DP stereoisomers are discussed herein. Chiral-T was evinced to exhibit high enantioselectivity, with highest α values attaining 16.5, 18.8 and 20.4 for Gly-Leu, dd/ll-Phe-Leu and ld/dl-Ala-Ala. At this point, Chiral-V did not exhibit enantioselectivity towards DP stereoisomers. The effect of MP composition on retention and enantioseparation of DPs was investigated. Lipophilicity of DPs was found to be an essential factor in the dependence of their retention vs. methanol concentration in МPs. Lipophobic DPs were eluted more quickly by water-rich solvents, with lipophilic DPs exhibiting an asymmetric U-shaped, or a descending dependence of retention factor vs. the methanol percentage on Chiral-T or Chiral-V, respectively. A theoretical model taking into account interaction of both solvents of a binary MP with both an analyte and adsorption sites was successfully applied so as to approximate and interpret the dependences of DP retention (monotonic and U-shaped) vs. a modifier content in MP. Water molecules were evinced to predominantly participate in competitive adsorption with DP molecules. The model predicted better solvation of lipophilic DPs by methanol and better solvation of lipophobic DPs by water. An attempt was made to verify the possibility of modeling by molecular docking the processes occurring during interaction between DP stereoisomers and CSPs, including consideration of the influence of competitive binding of eluent molecules in selector cavity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elena Reshetova reports financial support was provided by Russian Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Allostery, as seen in extant biology, governs the activity regulation of enzymes through the redistribution of conformational equilibria upon binding an effector. Herein, a minimal design is demonstrated where a dipeptide can exploit dynamic imine linkage to condense with simple aldehydes to access spherical aggregates as catalytically active states, which facilitates an orthogonal reaction due to the closer proximity of catalytic residues (imidazoles). The allosteric site (amine) of the minimal catalyst can concomitantly bind to an inhibitor via a dynamic exchange, which leads to the alternation of the energy landscape of the self-assembled state, resulting in downregulation of catalytic activity. Further, temporal control over allosteric regulation is realized via a feedback-controlled autonomous reaction network that utilizes the hydrolytic activity of the (in)active state as a function of time.

Cyclic dipeptides (CDPs) are crucial building blocks for a range of functional nanomaterials due to their simple chemical structure and high molecular stability. In this investigation, we synthesized a set of S-benzyl-L-cysteine-based CDPs (designated as P1-P6) and thoroughly examined their self-assembly behavior in a methanol-water solvent to elucidate the relationship between their structure and gelation properties. The hydrophobicity of the amino acids within the CDPs was gradually increased. The present study employed a comprehensive array of analytical techniques, including NMR, FT-IR, AFM, thioflavin-T, congo-red CD, X-ray crystallography, and biophysical calculations like Hirshfield Surface analysis and DFT analysis. These methods revealed that in addition to hydrogen bonding, the hydrophobic nature of the amino acid side chain significantly influences the propensity of CDPs to form hydrogels. Each CDP yielded distinct nanofibrillar networks rich in β-sheet structures, showcasing unique morphological features. Moreover, we explored the practical application of these CDP-based hydrogels in water purification by utilizing them to remove harmful organic dyes from contaminated water. This application underscores the potential of CDPs in addressing environmental challenges, offering a promising avenue for the future development of these materials in water treatment technologies., (© 2024 Wiley-VCH GmbH.)

Microcephaly, Guillain-Barré syndrome, and potential sexual transmission stand as prominent complications associated with Zika virus (ZIKV) infection. The absence of FDA-approved drugs or vaccines presents a substantial obstacle in combatting the virus. Furthermore, the inclusion of pregnancy in the pharmacological screening process complicates and extends the endeavor to ensure molecular safety and minimal toxicity. Given its pivotal role in viral assembly and maturation, the NS2B-NS3 viral protease emerges as a promising therapeutic target against ZIKV. In this context, a dipeptide inhibitor was specifically chosen as a control against 200 compounds for docking analysis. Subsequent molecular dynamics simulations extending over 200 ns were conducted to ascertain the stability of the docked complex and confirm the binding of the inhibitor at the protein's active site. The simulation outcomes exhibited conformity to acceptable thresholds, encompassing parameters such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), ligand-protein interaction analysis, ligand characterization, and surface area analysis. Notably, analysis of ligand angles bolstered the identification of prospective ligands capable of inhibiting viral protein activity and impeding virus dissemination. In this study, the integration of molecular docking and dynamics simulations has pinpointed the dipeptide inhibitor as a potential candidate ligand against ZIKV protease, thereby offering promise for therapeutic intervention against the virus., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ullah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Diphenylalanine(FF)-Zn self-assembly (FS) confined in covalent organic polymers (FS@COPs) with efficient fluorescence was synthesized for fluorescence sensing of biogenic amines, which was one of the most important indicators for monitoring food freshness. FS@COPs combined excellent biodegradability of self-assembled dipeptide with chemical stability, porosity and targeted site recognition of COPs. With an optimal excitation wavelength of 360 nm and an optimal emission wavelength of 450 nm, FS@COPs could be used as fluorescence probes to rapidly visualize and highly sensitive determination of tryptamine (Try) within 15 min, and the linear range was from 40 to 900 μg L -1 with a detection limit of 63.08 μg kg -1 . Importantly, the FS@COPs showed a high fluorescence quantum yield of 11.28%, and good stability, solubility, and selectivity, which could successfully achieve the rapid, accurate and highly sensitive identification of Try. Furthermore, we revealed the mechanism of FS@COPs for fluorescence sensing of targets. The FS@COPs system was applied to the fluorescence sensing of Try in real samples and showed satisfactory accuracy of 93.02%-105.25%., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Antioxidants agents play an essential role in the food industry for improving the oxidative stability of food products. In the last years, the search for new natural antioxidants has increased due to the potential high toxicity of chemical additives. Therefore, the synthesis and evaluation of the antioxidant activity in peptides is a field of current research. In this study, we performed a Quantitative Structure Activity Relationship analysis (QSAR) of cysteine-containing 19 dipeptides and 19 tripeptides. The main objective is to bring information on the relationship between the structure of peptides and their antioxidant activity. For this purpose, 1D and 2D molecular descriptors were calculated using the PaDEL software, which provides information about the structure, shape, size, charge, polarity, solubility and other aspects of the compounds. Different QSAR model for di- and tripeptides were developed. The statistic parameters for di-peptides model (R 2 train  = 0.947 and R 2 test  = 0.804) and for tripeptide models (R 2 train  = 0.923 and R 2 test  = 0.847) indicate that the generated models have high predictive capacity. Then, the influence of the cysteine position was analyzed predicting the antioxidant activity for new di- and tripeptides, and comparing them with glutathione. In dipeptides, excepting SC, TC and VC, the activity increases when cysteine is at the N-terminal position. For tripeptides, we observed a notable increase in activity when cysteine is placed in the N-terminal position., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs), have emerged as promising candidates in drug discovery. However, their effective delivery to the target tissues and cells remains a challenge, necessitating the development of suitable drug delivery technologies for ASOs to enable their practical application. In this study, we synthesized a library of chemically modified dipeptide-ASO conjugates using a recent synthetic method based on the Ugi reaction. We then conducted in vitro screening of this library using luciferase-expressing cell lines to identify ligands capable of enhancing ASO activity. Our findings suggest that N-(4-nitrophenoxycarbonyl)glycine may interact with the thiophosphate moiety of the phosphorothioate-modification in ASO. Through our screening efforts, we identified two ligands that modestly reduced luciferase luminescence in a cell type-selective manner. Furthermore, quantification of luciferase mRNA levels revealed that one of these promising dipeptide-ASO conjugates markedly suppressed luciferase RNA levels through its antisense effect in prostate-derived DU-145 cells compared to the ASOs without ligand modification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Ample biologically active peptides have been found, identified and modified for use in drug discovery to date. However, several factors, such as low metabolic stability due to proteolysis and non-specific interactions with multiple off-target molecules, might limit the therapeutic use of peptides. To enhance the stability and/or bioactivity of peptides, the development of "peptidomimetics," which mimick peptide molecules, is considered to be idealistic. Hence, chloroalkene dipeptide isosteres (CADIs) was designed, and their synthetic methods have been developed by us. Briefly, in a CADI an amide bond in peptides is replaced with a chloroalkene structure. CADIs might be superior mimetics of amide bonds because the Van der Waals radii (VDR) and the electronegativity value of a chlorine atom are close to those of the replaced oxygen atom. By a developed method of the "liner synthesis", N-tert-butylsulfonyl protected CADIs can be synthesized via a key reaction involving diastereoselective allylic alkylation using organocopper reagents. On the other hand, by a developed method of the "convergent synthesis", N-fluorenylmethoxycarbonyl (Fmoc)-protected carboxylic acids can be also constructed based on N- and C-terminal analogues from corresponding amino acid starting materials via an Evans syn aldol reaction and the Ichikawa allylcyanate rearrangement reaction involving a [3.3] sigmatropic rearrangement. Notably, CADIs can also be applied for Fmoc-based solid-phase peptide synthesis and therefore introduced into bioactive peptides including as the Arg-Gly-Asp (RGD) peptide and the amyloid β fragment Lys-Leu-Val-Phe-Phe (KLVFF) peptide, which are correlated with cell attachment and Alzheimer's disease (AD), respectively. These CADI-containing peptidomimetics stabilized the conformation and enhanced the potency of the cyclic RGD peptide and the cyclic KLVFF peptide., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The identification of anticancer peptides (ACPs) is crucial, especially in the development of peptide-based cancer therapy. The classical models such as Split Amino Acid Composition (SAAC) and Pseudo Amino Acid Composition (PseAAC) lack the incorporation of feature representation. These advancements improve the predictive accuracy and efficiency of ACP identification. Thus, the effort of this research is to propose and develop an advanced framework based on feature extraction. Thus, to achieve this objective herein we propose an Extended Dipeptide Composition (EDPC) framework. The proposed EDPC framework extends the dipeptide composition by considering the local sequence environment information and reforming the CD-HIT framework to remove noise and redundancy. To measure the accuracy, we have performed several experiments. These experiments were employed using four famous machine learning (ML) algorithms named; Support Vector Machine (SVM), Decision Tree (DT), Random Forest (RF), and K Nearest Neighbor (KNN). For comparisons, we have used accuracy, specificity, sensitivity, precision, recall, and F1-Score as evaluation criteria. The reliability of the proposed framework is further evaluated using statistical significance tests. As a result, the proposed EDPC framework exhibited enhanced performance than SAAC and PseAAC, where the SVM model delivered the highest accuracy of 96. 6% and significant enhancements in specificity, sensitivity, precision, and F1-score over multiple datasets. Due to the incorporation of enhanced feature representation and the incorporation of local and global sequence profiles proposed EDPC achieves higher classification performance. The proposed frameworks can deal with noise and also duplicating features. These are accompanied by a wide range of feature representations. Finally, our proposed framework can be used for clinical applications where ACP identification is essential. Future works will include extending to a larger variety of datasets, incorporating tertiary structural information, and using deep learning techniques to improve the proposed EDPC., (© 2024. The Author(s).)

The ability to accurately predict protein-protein interactions is critically important for understanding major cellular processes. However, current experimental and computational approaches for identifying them are technically very challenging and still have limited success. We propose a new computational method for predicting protein-protein interactions using only primary sequence information. It utilizes the concept of physicochemical similarity to determine which interactions will most likely occur. In our approach, the physicochemical features of proteins are extracted using bioinformatics tools for different organisms. Then they are utilized in a machine-learning method to identify successful protein-protein interactions via correlation analysis. It was found that the most important property that correlates most with the protein-protein interactions for all studied organisms is dipeptide amino acid composition (the frequency of specific amino acid pairs in a protein sequence). While current approaches often overlook the specificity of protein-protein interactions with different organisms, our method yields context-specific features that determine protein-protein interactions. The analysis is specifically applied to the bacterial two-component system that includes histidine kinase and transcriptional response regulators, as well as to the barnase-barstar complex, demonstrating the method's versatility across different biological systems. Our approach can be applied to predict protein-protein interactions in any biological system, providing an important tool for investigating complex biological processes' mechanisms., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The abiotic synthesis of peptides, widely regarded as one of the key chemical reactions on the prebiotic Earth, is thermodynamically constrained in solution. Herein, a simulation of the lightning phenomenon on the sea surface using bubble bursting and arc plasma under ambient conditions enables dipeptide formation of six amino acids with conversion ratios ranging from 2.6 % to 25.5 %. Additionally, we observed the formation of biologically active tripeptides and investigated the stereoselectivity of the dipeptide formation reaction. By utilizing a mixture of 20 amino acids in the reaction, 102 possible dipeptides were generated. These results establish experimental constructions to mimic achievable prebiotic conditions and provide a credible pathway for endogenous biopolymer synthesis on prebiotic Earth., (© 2024 Wiley-VCH GmbH.)

Recent renewed interest in the possibility of life in the acidic clouds of Venus has led to new studies on organic chemistry in concentrated sulfuric acid. We have previously found that the majority of amino acids are stable in the range of Venus' cloud sulfuric acid concentrations (81% and 98% w/w, the rest being water). The natural next question is whether dipeptides, as precursors to larger peptides and proteins, could be stable in this environment. We investigated the reactivity of the peptide bond using 20 homodipeptides and find that the majority of them undergo solvolysis within a few weeks, at both sulfuric acid concentrations. Notably, a few exceptions exist. HH and GG dipeptides are stable in 98% w/w sulfuric acid for at least 4 months, while II, LL, VV, PP, RR and KK resist hydrolysis in 81% w/w sulfuric acid for at least 5 weeks. Moreover, the breakdown process of the dipeptides studied in 98% w/w concentrated sulfuric acid is different from the standard acid-catalyzed hydrolysis that releases monomeric amino acids. Despite a few exceptions at a single concentration, no homodipeptides have demonstrated stability across both acid concentrations studied. This indicates that any hypothetical life on Venus would likely require a functional substitute for the peptide bond that can maintain stability throughout the range of sulfuric acid concentrations present., (© 2024. The Author(s).)

The synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), a rapidly advancing therapeutic approach in oncology. The conventional method for synthesizing cathepsin B-labile dipeptide linkers, which are commonly used in ADC development, involves the solution-phase assembly of cathepsin B-sensitive dipeptides, followed by the installation of self-immolative para -aminobenzyl carbonate to facilitate the attachment of potent cytotoxic payloads. However, this approach is often low yield and laborious, especially when extending the peptide chain with components like glutamic acid to improve mouse serum stability or charged amino acids or poly(ethylene glycol) moieties to enhance linker hydrophilicity. Here, we introduce a novel approach utilizing late-stage desulfurization chemistry, enabling safe, facile, and cost-effective access to the cathepsin B-cleavable linker, Val-Ala-PABC-MMAE, on resin for the first time.

Bioactive peptides derived from food are promising health-promoting ingredients that can be used in functional foods and nutraceutical formulations. In addition to the potency towards the selected therapeutic target, the bioavailability of bioactive peptides is a major factor regarding clinical efficacy. We have previously shown that a low molecular weight peptide fraction (LMWPF) from poultry by-product hydrolysates possesses angiotensin-1-converting enzyme (ACE-1) and dipeptidyl-peptidase 4 (DPP4) inhibitory activities. The present study aimed to investigate the bioavailability of the bioactive peptides in the LMWPF. Prior to the investigation of bioavailability, a dipeptide YA was identified from this fraction as a dual inhibitor of ACE-1 and DPP4. Gastrointestinal (GI) stability and intestinal absorption of the bioactive peptides ( i.e. , YA as well as two previously reported bioactive dipeptides (VL and IY)) in the LMWPF were evaluated using the INFOGEST static in vitro digestion model and intestinal Caco-2 cell monolayer, respectively. Analysis of peptides after in vitro digestion confirmed that the dipeptides were resistant to the simulated GI conditions. After 4 hours of incubation, the concentration of the peptide from the apical side of the Caco-2 cell monolayer showed a significant decrease. However, the corresponding absorbed peptides were not detected on the basolateral side, suggesting that the peptides were not transported across the intestinal monolayer but rather taken up or metabolized by the Caco2 cells. Furthermore, when analyzing the gene expression of the Caco-2 cells upon peptide stimulation, a down-regulation of peptide transporters, the transcription factor CDX2 , and the tight junction protein-1 ( TJP1 ) was observed, suggesting the specific effects of the peptides on the Caco-2 cells. The study demonstrated that bioactive dipeptides found in the LMWPF were stable through in vitro GI digestion; however, the overall bioavailability may be hindered by inadequate uptake across the intestinal barrier.

Accurately describing long-range interactions is a significant challenge in molecular dynamics (MD) simulations of proteins. High-quality long-range potential is also an important component of the range-separated machine learning force field. This study introduces a comprehensive asymptotic parameter database encompassing atomic multipole moments, polarizabilities, and dispersion coefficients. Leveraging active learning, our database comprehensively represents protein fragments with up to 8 heavy atoms, capturing their conformational diversity with merely 78,000 data points. Additionally, the E(3) neural network (E3NN) is employed to predict the asymptotic parameters directly from the local geometry. The E3NN models demonstrate exceptional accuracy and transferability across all asymptotic parameters, achieving an R 2 of 0.999 for both protein fragments and 20 amino acid dipeptide test sets. The long-range electrostatic and dispersion energies can be obtained using the E3NN-predicted parameters, with an error of 0.07 and 0.02 kcal/mol, respectively, when compared to symmetry-adapted perturbation theory (SAPT). Therefore, our force fields demonstrate the capability to accurately describe long-range interactions in proteins, paving the way for next-generation protein force fields.

Context: The paper considers the features of the structure and dipole moments of several amino acids and their dipeptides which play an important role in the formation of the peptide nanotubes based on them. The influence of the features of their chirality (left L and right D) and the alpha-helix conformations of amino acids are taken into account. In particular, amino acids with aromatic rings, such as phenylalanine (Phe/F), and branched-chain amino acids (BCAAs)-leucine (Leu/L) and isoleucine (Ile/I)-as well as corresponding dipeptides (diphenylalanine (FF), dileucine (LL), and diisoleucine (II)) are considered. The main features and properties of these dipeptide structures and peptide nanotubes (PNTs), based on them, are investigated using computational molecular modeling and quantum-chemical semi-empirical calculations. Their polar, piezoelectric, and photoelectronic properties and features are studied in detail. The results of calculations of dipole moments and polarization, as well as piezoelectric coefficients and band gap width, for different types of helical peptide nanotubes are presented. The calculated values of the chirality indices of various nanotubes are given, depending on the chirality of the initial dipeptides-the results obtained are consistent with the law of changes in the type of chirality as the hierarchy of molecular structures becomes more complex. The influence of water molecules in the internal cavity of nanotubes on their physical properties is estimated. A comparison of the results of these calculations by various computational methods with the available experimental data is presented and discussed., Method: The main tool for molecular modeling of all studied nanostructures in this work was the HyperChem 8.01 software package. The main approach used here is the Hartree-Fock (HF) self-consistent field (SCF) with various quantum-chemical semi-empirical methods (AM1, PM3, RM1) in the restricted Hartree-Fock (RHF) and in the unrestricted Hartree-Fock (UHF) approximations. Optimization of molecular systems and the search for their optimal geometry is carried out in this work using the Polak-Ribeire algorithm (conjugate gradient method), which determines the optimized geometry at the point of their minimum total energy. For such optimized structures, dipole moments D and electronic energy levels (such as E HOMO and E LUMO ), as well as the band gap E g  = E LUMO  - E HOMO , were then calculated. For each optimized molecular structure, the volume was calculated using the QSAR program implemented also in the HyperChem software package., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chromatographic behavior of novel chiral stationary phases with bonded selectors based on Cinchona alkaloids modified with dipeptides was studied using dipeptides as probe molecules. Buffer-free and salt containing hydro-organic solutions were used as the mobile phases. The selectors exhibit pseudoenantiomeric behavior with respect to the L/D or LL/DD enantiomers and do not behave so with respect to the LD/DL enantiomers. The alkaloid part of the selectors is the driver of enantioselectivity, while the dipeptide substituent plays a modulating role. The quinidine-based selectors demonstrate stronger adsorption affinity and higher enantioselectivity as compared to the quinine-based selectors. The dipeptide analytes containing a glycyl fragment are weaker retained and their enantiomers are worse separated comparing to dipeptides with both units being larger amino acids. Moreover, a phenyl group in the structure of a dipeptide analyte facilitates enantioseparation. The effect of the mobile phase composition on retention depends on the hydrophobicity of an analyte. Hydrophobic dipeptides are better eluted by methanol-rich solvents, hydrophilic dipeptides are better eluted with water-rich solvents, and dipeptides with an intermediate hydrophobicity demonstrate a U-shaped or more complicated dependence of the retention factor on the percentage of methanol. Even a small buffer addition to the mobile phase decreases retention, but the ion-exchange mechanism was not confirmed. The effect of an electrolyte is rather due to the shielding of the charged groups of the selector reducing thereby electrostatic interaction between the selector and analyte. Efficiency of the novel columns is comparable to that of other brush-type chiral columns, the highest achieved number of the theoretical plates per 1 m varying between 30,000 and 40,000., Competing Interests: Declaration of competing interest The authors report no financial interest/personal relationship which may be considered as potential competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Advantages like biocompatibility, biodegradability and tunability allowed the exploitation of peptides and peptidomimetics as versatile therapeutic or diagnostic agents. Because of their selectivity towards transmembrane receptors or cell membranes, peptides have also been identified as suitable molecules able to deliver in vivo macromolecules, proteins or nucleic acids. However, after the identification of the homodimer diphenylalanine (FF) as an aggregative motif inside the Aβ 1-42 polypeptide, short and ultrashort peptides have been studied as building blocks for the fabrication of supramolecular, ordered nanostructures for applications in biotechnological, biomedical and industrial fields. In this perspective, many hybrid molecules that combine FF with other chemical entities have been synthesized and characterized. Two novel hybrid derivatives (tFaF and cFgF), in which the FF homodimer is alternated with the peptide-nucleic acid (PNA) heterodimer "g-c" (guanine-cytosine) or "a-t" (adenine-thymine) and their dimeric forms (tFaF) 2 and (cFgF) 2 were synthesized. The structural characterization performed by circular dichroism (CD), Fourier transform infrared (FTIR) and fluorescence spectroscopies highlighted the capability of all the FF-PNA derivatives to self-assemble into β-sheet structures. As a consequence of this supramolecular organization, the resulting aggregates also exhibit optoelectronic properties already reported for other similar nanostructures. This photoemissive behavior is promising for their potential applications in bioimaging., (© 2024 European Peptide Society and John Wiley & Sons Ltd.)

L-Alanyl-L-tyrosine (L-Ala-Tyr) is a dipeptide formed by the condensation of L-alanine methyl ester and L-tyrosine. After entering the body, it can be rapidly broken down to release tyrosine. In this study, L-Ala-Tyr was successfully prepared by using α-ester acyltransferase as biocatalyst and alanine methyl ester (L-Ala-OMe) and tyrosine (L-Tyr) as acyl donor and nucleophile, respectively. The dipeptide yield was increased from 15 to 50% by optimizing the conditions: boric acid-borax (0.2 mol/L), 30°C, pH 9.5, 2:1 acyl donor to nucleophile ratio, DES (ChCl/urea), and 15%(v/v) water content. The catalytic product is then isolated and purified. The structure of the product was identified by high-performance liquid chromatography, mass spectrometry, proton nuclear magnetic resonance, and carbon spectroscopy. Its biological activity was preliminarily determined by the B16-F10 mouse melanoma cell model. The results showed that the purity of L-Ala-Tyr prepared by the separation and purification method of this study was 96.8%, and the mass spectrometry and nuclear magnetic resonance spectroscopy showed that the structure of the peptide was consistent with the expected structure. In addition, the preliminary physiological activity identification results show that L-Ala-Tyr has no toxic effect on cells in the concentration range of 100-800 μmol·L -1 , and at the optimal concentration, compared with the positive control 8-methoxypsoralen, it can promote the production of melanin., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tactile sensing requires integrated detection platforms with distributed and highly sensitive haptic sensing capabilities along with biocompatibility, aiming to replicate the physiological functions of the human skin and empower industrial robotic and prosthetic wearers to detect tactile information. In this regard, short peptide-based self-assembled hydrogels show promising potential to act as bioinspired supramolecular substrates for developing tactile sensors showing biocompatibility and biodegradability. However, the intrinsic difficulty to modulate the mechanical properties severely restricts their extensive employment. Herein, by controlling the self-assembly of 9-fluorenylmethoxycarbonyl-modifid diphenylalanine (Fmoc-FF) through introduction of polyethylene glycol diacrylate (PEGDA), wider nanoribbons are achieved by untwisting from well-established thinner nanofibers, and the mechanical properties of the supramolecular hydrogels can be enhanced 10-fold, supplying bioinspired supramolecular encapsulating substrate for tactile sensing. Furthermore, by doping with poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) and 9-fluorenylmethoxycarbonyl-modifid 3,4-dihydroxy-l-phenylalanine (Fmoc-DOPA), the Fmoc-FF self-assembled hydrogels can be engineered to be conductive and adhesive, providing bioinspired sensing units and adhesive layer for tactile sensing applications. Therefore, the integration of these modules results in peptide hydrogelation-based tactile sensors, showing high sensitivity and sustainable responses with intrinsic biocompatibility and biodegradability. The findings establish the feasibility of developing programmable peptide self-assembly with adjustable features for tactile sensing applications., (© 2024 Wiley‐VCH GmbH.)

Two new cyclic dipeptides, paranazzamides A (1) and B (2) containing a C7-prenylated tryptophan, were isolated from a culture broth of snake fungal disease-isolate Paranannizziopsis sp. UH-21. This is the first report on the new secondary metabolites from Paranannizziopsis sp. The planar structures of 1 and 2 were elucidated using various spectroscopic techniques including MS and 1D/2D NMR. The absolute configuration of 1 was assigned by comparison with the synthesized compound. Compounds 1 and 2 exhibited no antifungal activity, no antibacterial activity, and no cytotoxic activity even at a concentration of 128 µg ml -1 , whereas 1 and 2 exhibited amphotericin B potentiating activity against Candida auris in combination treatment., (© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Purpose: A series of new 68 Ga-labeled tracers based on [ 68 Ga]Ga-PSMA-617 were developed to augment the tumor-to-kidney ratio and reduce the activity accumulation in bladder, ultimately minimize radiation toxicity to the urinary system., Methods: We introduced quinoline group, phenylalanine and decanoic acid into different tracers to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Their binding affinity onto LNCaP cells was determined through in vitro saturation assays and competition binding assays. In vivo metabolic study, PET imaging and biodistribution experiment were performed in LNCaP tumor-bearing B-NSG male mice. The most promising tracer was selected for first-in-human study., Results: Four radiotracers were synthesized with radiochemical purity (RCP) > 95% and molar activity in a range of 20.0-25.5 GBq/μmol. The binding affinities (K i ) of TWS01, TWS02 to PSMA were in the low nanomolar range (< 10 nM), while TWS03 and TWS04 exhibited binding affinities with K i  > 20 nM (59.42 nM for TWS03 and 37.14 nM for TWS04). All radiotracers exhibited high stability in vivo except [ 68 Ga]Ga-TWS03. Micro PET/CT imaging and biodistribution analysis revealed that [ 68 Ga]Ga-TWS02 enabled clear tumor visualization in PET images at 1.5 h post-injection, with higher tumor-to-kidney ratio (T/K, 0.93) and tumor-to-muscle ratio (T/M, 107.62) compared with [ 68 Ga]Ga-PSMA-617 (T/K: 0.39, T/M: 15.01) and [ 68 Ga]Ga-PSMA-11 (T/K: 0.15, T/M: 24.00). In first-in-human study, [ 68 Ga]Ga-TWS02 effectively detected PCa-associated lesions including primary and metastatic lesions, with lower accumulation in urinary system, suggesting that [ 68 Ga]Ga-TWS02 might be applied in the detection of bladder invasion, with minimized radiation toxicity to the urinary system., Conclusion: Introduction of quinoline group, phenylalanine and decanoic acid into different tracers can modulate the binding affinity and pharmacokinetics of PSMA in vivo. [ 68 Ga]Ga-TWS02 showed high binding affinity to PSMA, excellent pharmacokinetic properties and clear imaging of PCa-associated lesions, making it a promising radiotracer for the clinical diagnosis of PCa. Moreover, TWS02 with a chelator DOTA could also label 177 Lu and 225 Ac, which could be used for PCa treatment without significant side effects., Trial Registration: The clinical evaluation of this study was registered On October 30, 2021 at https://www.chictr.org.cn/ (No: ChiCTR2100052545)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The marked success of prostate-specific membrane antigen (PSMA)-targeting radioligands with albumin binder (ALB) is attributed to the improvement of blood retention and tumor accumulation. [ 111 In]In-PNT-DA1, our PSMA-targeting radioligand with ALB, also achieved improved tumor accumulation due to its prolonged blood retention. Although the advantage of ALBs is related to their reversible binding to albumin, the relationship between albumin-binding and tumor accumulation of PSMA-targeting radioligands remains unclear because of the lack of information about radioligands with stronger albumin-binding than ALBs. In this study, we designed and synthesized [ 111 In]In-PNT-DM-HSA, a new radioligand that consists of a PSMA-targeting radioligand covalently bound to albumin. The pharmacokinetics of [ 111 In]In-PNT-DM-HSA was compared with those of [ 111 In]In-PNT-DA1 and [ 111 In]In-PSMA-617, a non-ALB-conjugated radioligand, to evaluate the relationship between albumin-binding and tumor accumulation., Method: The [ 111 In]In-PNT-DM-HSA was prepared by incubation of [ 111 In]In-PNT-DM, a PSMA-targeting radioligand including a maleimide group, and human serum albumin (HSA). The ability of [ 111 In]In-PNT-DM-HSA was evaluated by in vitro assays. A biodistribution study using LNCaP tumor-bearing mice was conducted to compare the pharmacokinetics of [ 111 In]In-PNT-DM-HSA, [ 111 In]In-PNT-DA1, and [ 111 In]In-PSMA-617., Results: The [ 111 In]In-PNT-DM-HSA was obtained at a favorable radiochemical yield and high radiochemical purity. In vitro assays revealed that [ 111 In]In-PNT-DM-HSA had fundamental characteristics as a PSMA-targeting radioligand interacting with albumin covalently. In a biodistribution study, [ 111 In]In-PNT-DM-HSA and [ 111 In]In-PNT-DA1 showed higher blood retention than [ 111 In]In-PSMA-617. On the other hand, the tumor accumulation of [ 111 In]In-PNT-DA1 was much higher than [ 111 In]In-PNT-DM-HSA and [ 111 In]In-PSMA-617., Conclusions: These results indicate that the moderate reversible binding of ALB with albumin, not covalent binding, may play a critical role in enhancing the tumor accumulation of PSMA-targeting radioligands., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Phosphorylated peptides are instrumental in studying protein phosphorylation events. In the present study, Raman optical activity (ROA) is employed to elucidate the structure of a dipeptide, L-alanyl-L-glutamine (L-Ala-L-Gln) and its two differently alkylated N-phosphorylated derivatives. Theoretical simulations were conducted to aid the interpretation of peptide conformation variations upon phosphorylation, and of the measured Raman and ROA spectra. Induced circularly polarized luminescence (CPL) was also recorded in solution, in the presence of a simple europium aqua ion. As the spectra are peptide specific, this type of stereochemical analysis is expected to aid identification of the phosphorylation sites also in other peptides and possibly proteins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Twelve new sulphonamide (Cys-Gly) dipeptide carboxamide derivatives 17a-17l were designed, prepared and characterized through spectroscopic techniques and their pharmacological properties investigated. The molecular docking analyses revealed good interactions of the derivatives with the desired amino residues active pockets. In vitro antimicrobial, in vivo antimalarial, haematological and other related tests (liver and kidney) were also conducted. Compounds 17b exhibited good minimum inhibitory concentration (MIC) results (0.9-11) mg/mL for the studied organisms when compared with ciprofloxacin and fluconazole. Derivatives 17a -17l showed parasitaemia inhibition in the range (31.11-67.78) % on the fourth day after treating the animals with 40 mg/kg of the compounds. Derivative 17b also displayed the highest parasitaemia inhibition (67.78 %) comparable with the standard (Lumenfantrine) 75.27 %. The prepared derivatives showed promising pharmacological properties with regards to hematological, liver and kidney function tests., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Reduced glutathione (GSH) is an endogenous tripeptide antioxidant which plays a crucial role in a variety of physiological and pathological activities. Although GSH is not present in any FDA-approved drug product, GSH dietary supplement products and compounded GSH drugs are available to patients in the US. Several incidents of toxicity have occurred in recent years due to endotoxin or otherwise contaminated GSH in compounded drugs. Efficient and sensitive analytical methods are needed for assessing and ensuring the quality of GSH substance and associated drug or dietary supplement products. Impurities A (L-cysteinylglycine), B (cysteine), C (oxidized L-glutathione) and D (γ-L-glutamyl-L-cysteine) are the main related impurities for GSH drug substance which have been detected and quantified by capillary electrophoresis and qNMR analytical procedures. However, there are no reported HPLC methods for detecting or quantifying the three main related impurities A, B and D even though numerous HPLC analytical methods have been reported for analyzing GSH and impurity C. In this report, an isocratic HPLC-UV analytical procedure was developed and validated for separating and identifying GSH and related impurities A-D as well as a newly identified degradant, L-pyroglutamic acid (pGlu), within 10 minutes with resolution (R S ) more than 3. The LOD and LOQ were determined to be 0.02 % w/w and 0.05 % w/w, respectively, for impurities A-D and pGlu. Importantly, the optimized HPLC analytical procedure for GSH assay does not have interference from impurities A, B and D, providing highly specific results compared to the commonly used iodine titration method. The newly validated analytical procedure was applied to assess different commercial GSH bulk substance samples. The results suggest that the analytical procedure described in this work is suitable for quality assessment of GSH samples., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Qin Shu reports financial support was provided by US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Qin Shu reports a relationship with US Food and Drug Administration that includes: employment and funding grants. Mary Schleiff, Jingfan Chen, Cynthia Sommers, Jingyue Yang, Xiaohui Shen, Jason D. Rodriguez, David A. Keire report a relationship with US Food and Drug Administration that includes: employment, (Published by Elsevier B.V.)

The development of lipid nanoparticles (LNPs) has enabled the clinical application of small interfering ribonucleic acid (siRNA)-based therapies. Accordingly, various unique ionizable lipids have been explored for efficient siRNA delivery. However, safety concerns related to the structure of ionizable lipids have been raised. Here, we developed a pH-responsive dipeptide-conjugated lipid (DPL) for efficient, high safety siRNA delivery. We synthesized a DPL library by varying the dipeptide sequence and established a strong correlation between the knockdown efficiency of the DPL-based LNPs and the dipeptide sequence. The LNPs prepared with a DPL containing arginine (R) and glutamic acid (E) (DPL-ER) exhibited the highest knockdown efficiency. In addition, the DPL-ER-based LNPs with relatively long lipid tails (DPL-ER-C22:C22) exhibited a higher knockdown efficiency than those with short ones (DPL-ER-18:C18). The zeta potential of the DPL-ER-C22:C22-based LNPs increased as the pH decreased from 7.4 (physiological condition) to 5.5 (endosomal condition). Importantly, the DPL-ER-C22:C22-based LNPs exhibited a higher knockdown efficiency than the LNPs prepared using commercially available ionizable lipids. These results suggest that the DPL-based LNPs are safe and efficient siRNA delivery carriers., Competing Interests: Declaration of competing interest The authors have no competing interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cyclic glycine-proline ( cGP ), a prevalent marine cyclic dipeptide, possesses a distinct pyrrolidine-2,5-dione scaffold, which contributes to the chemical diversity and broad bioactivities of cGP . The diverse sources from marine-related, endogenous biological, and synthetic pathways and the in vitro and in vivo activities of cGP are reviewed. The potential applications for cGP are also explored. In particular, the pivotal roles of cGP in regulating insulin-like growth factor-1 homeostasis, enhancing neuroprotective effects, and improving neurotrophic function in central nervous system diseases are described. The potential roles of this endogenous cyclic peptide in drug development and healthcare initiatives are also highlighted. This review underscores the significance of cGP as a fundamental building block in drug discovery with exceptional drug-like properties and safety. By elucidating the considerable value of cGP , this review aims to reignite interest in cGP -related research within marine medicinal chemistry and synthetic biology.

Relaxation times of nuclear spins often serve as a valuable source of information on the dynamics of various biochemical processes. Measuring relaxation as a function of the external magnetic field turned out to be extremely useful for the studies of weak ligand-protein interactions. We demonstrate that observing the relaxation of the long-lived spin order instead of longitudinal magnetization extends the capability of this approach. We studied the field-dependent relaxation of the longitudinal magnetization and the singlet order (SO) of methylene protons in alanine-glycine dipeptide and citrate in the presence of human serum albumin (HSA). As a result, SO relaxation proved to be more sensitive to ligand-protein interaction, providing higher relaxation contrast for various HSA concentrations. To assess the parameters of the binding process in more details, we utilized a simple analytical relaxation model to fit the experimental field dependences for both SO and T 1 relaxation. We also tested the validity of our approach in the experiments with trimethylsilylpropanoic acid (TSP) used as a competitor in ligand binding with HSA.

The utilization of the glycated amino acids formyline and pyrraline as well as their peptide-bound derivatives by 14 Saccharomyces yeasts, including 6 beer yeasts (bottom and top fermenting), one wine yeast, 6 strains isolated from natural habitats and one laboratory reference yeast strain (wild type) was investigated. All yeasts were able to metabolize glycated amino acids via the Ehrlich pathway to the corresponding Ehrlich metabolites. While formyline and small amounts of pyrraline entered the yeast cells via passive diffusion, the amounts of dipeptide-bound MRPs, especially the dipeptides glycated at the C-terminus, decreased much faster, indicating an uptake into the yeast cells. Furthermore, the glycation-mediated hydrophobization in general leads to an faster degradation rate compared to the native lysine dipeptides. While the utilization of free formyline is yeast-specific, the amounts of (glycated) dipeptides decreased faster in the presence of brewer's yeasts, which also showed a higher formation rate of Ehrlich metabolites compared to naturally isolated strains. Due to rapid uptake of alanyl dipeptides, it can be assumed that the Ehrlich enzyme system of naturally isolated yeasts is overloaded and the intracellularly released MRP is primarily excreted from the cell. This indicates adaptation of technologically used yeasts to (glycated) dipeptides as a nitrogen source., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Nitric oxide (NO) donating drugs such as organic nitrates have been used to treat cardiovascular diseases for more than a century. These donors primarily produce NO systemically. It is however sometimes desirable to control the amount, location, and time of NO delivery. We present the design of a novel pH-sensitive NO release system that is achieved by the synthesis of dipeptide diphenylalanine (FF) and graphene oxide (GO) co-assembled hybrid nanosheets (termed as FF@GO) through weak molecular interactions. These hybrid nanosheets were characterised by using X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, zeta potential measurements, X-ray photoelectron spectroscopy, scanning and transmission electron microscopies. The weak molecular interactions, which include electrostatic, hydrogen bonding and π-π stacking, are pH sensitive due to the presence of carboxylic acid and amine functionalities on GO and the dipeptide building blocks. Herein, we demonstrate that this formulation can be loaded with NO gas with the dipeptide acting as an arresting agent to inhibit NO burst release at neutral pH; however, at acidic pH it is capable of releasing NO at the rate of up to 0.6 μM per minute, comparable to the amount of NO produced by healthy endothelium. In conclusion, the innovative conjugation of dipeptide with graphene can store and release NO gas under physiologically relevant concentrations in a pH-responsive manner. pH responsive NO-releasing organic-inorganic nanohybrids may prove useful for the treatment of cardiovascular diseases and other pathologies., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The investigation of collagen hydrolysates (CHs) is essential due to their widespread use in health, cosmetic, and therapeutic industries, attributing to the presence of bioactive dipeptides (DPs) and tripeptides (TPs). This study developed a novel targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with propyl chloroformate (PCF) derivatization to measure three bioactive peptides-Hydroxyprolyl-glycine (Hyp-Gly), Glycyl-prolyl-hydroxyproline (Gly-Pro-Hyp), and Prolyl-hydroxyproline (Pro-Hyp)-in CHs, with strong correlation coefficients (0.992, 1.000, and 0.995, respectively) and low limits of detection (LODs) of 1.40, 0.14, and 1.16 µM, respectively. Untargeted data-dependent acquisition (DDA) analyses measured peptide size distribution, while amino acid analysis assessed nutritional content. The analysis of ten commercial CHs revealed similar amino acid profiles but varied peptide lengths, indicating diverse hydrolysis conditions. Products with higher proportions of smaller peptides showed elevated levels of the targeted bioactive peptides, suggesting that a smaller peptide size may increase bioactivity. These findings can inform the optimization of CH supplements, providing consumers with detailed peptide content for more informed choices. Data are available via ProteomeXchange with the identifier PXD051699.

Conformational dynamics play a crucial role in determining the behavior of the biomolecules. Polarizable force fields, such as AMOEBA, can accurately capture electrostatic interactions underlying the conformational space. However, applying a polarizable force field in molecular dynamics (MD) simulations can be computationally expensive, especially in studying long-time-scale dynamics. To overcome this challenge, we incorporated the AMOEBA potential with Milestoning, an enhanced sampling method in this work. This integration allows us to efficiently sample the rare and important conformational states of a biomolecule by using many short and independent molecular dynamics trajectories with the AMOEBA force field. We applied this method to investigate the conformational dynamics of alanine dipeptide, DNA, and RNA A-B form conversion. Well-converged thermodynamic and kinetic properties were obtained, including the free energy difference, mean first passage time, and critical transitions between states. Our results demonstrate the power of integrating polarizable force fields with enhanced sampling methods in quantifying the thermodynamic and kinetic properties of biomolecules at the atomic level.

Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [ 177 Lu]Lu-PSMA-617 (Pluvicto), have been shown to accumulate in salivary glands and kidneys, potentially leading to undesired side effects. As unwanted accumulation in normal organs may derive from the cross-reactivity of PSMA ligands to glutamate carboxypeptidase III (GCPIII), it may be convenient to block this interaction with GCPIII-selective ligands. Parallel screening of a DNA-encoded chemical library (DEL) against GCPIII and PSMA allowed the identification of GCPIII binders. Structure-activity relationship (SAR) studies resulted in the identification of nanomolar GCPIII ligands with up to 1000-fold selectivity over PSMA. We studied the ability of GCPIII ligands to counteract the binding of [ 177 Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.

Sialin, a member of the solute carrier 17 (SLC17) transporter family, is unique in its ability to transport not only sialic acid using a pH-driven mechanism, but also transport mono and diacidic neurotransmitters, such as glutamate and N-acetylaspartylglutamate (NAAG), into synaptic vesicles via a membrane potential-driven mechanism. While most transporters utilize one of these mechanisms, the structural basis of how Sialin transports substrates using both remains unclear. Here, we present the cryogenic electron-microscopy structures of human Sialin: apo cytosol-open, apo lumen-open, NAAG-bound, and inhibitor-bound. Our structures show that a positively charged cytosol-open vestibule accommodates either NAAG or the Sialin inhibitor Fmoc-Leu-OH, while its luminal cavity potentially binds sialic acid. Moreover, functional analyses along with molecular dynamics simulations identify key residues in binding sialic acid and NAAG. Thus, our findings uncover the essential conformational states in NAAG and sialic acid transport, demonstrating a working model of SLC17 transporters., (© 2024. The Author(s).)

Oral dispersible films have received broad interest due to fast drug absorption and no first-path metabolism, leading to high bioavailability and better patient compliance. Saxagliptin (SXG) is an antidiabetic drug that undergoes first-path metabolism, resulting in a less active metabolite, so the development of SXG oral dispersible films (SXG-ODFs) improves SXG bioavailability. The formula optimisation included a response surface experimental design and the impact of three formulation factors, the type and concentration of polymer and plasticiser concentration on in-vitro disintegration time and folding endurance. Two optimised SXG-ODFs prepared using either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose were investigated. SXG-ODFs prepared with PVA demonstrated a superior rapid disintegration time, ranging from 17 to 890 s, with the fastest disintegration time recorded at 17 s. These short durations can be attributed to the hydrophilic nature of PVA, facilitating rapid hydration and disintegration upon contact with saliva. Additionally, PVA-based films displayed remarkable folding endurance, surpassing 200 folds without rupture, indicating flexibility and stability. The high tensile strength of PVA-based films further underscores their robust mechanical properties, with tensile strength values reaching up to 4.53 MPa. SXG exhibits a UV absorption wavelength of around 212 nm, posing challenges for traditional quantitative spectrophotometric analysis, so a polyaniline nanoparticles-based solid-contact screen-printed ion-selective electrode (SP-ISE) was employed for the determination of SXG release profile effectively in comparison to HPLC. SP-ISE showed a better real-time release profile of SXG-ODFs, and the optimised formula showed lower blood glucose levels than commercial tablets., (© 2024. The Author(s).)

Quantifying the conformational ensembles of biomolecules is fundamental to describing mechanisms of processes such as protein folding, interconversion between folded states, ligand binding, and allosteric regulation. Accurate quantification of these ensembles remains a challenge for conventional molecular simulations of all but the simplest molecules due to insufficient sampling. Enhanced sampling approaches, such as metadynamics, were designed to overcome this challenge; however, the nonuniform frame weights that result from many of these approaches present an additional challenge to ensemble quantification techniques such as Markov State Modeling or structural clustering. Here, we present rigorous inclusion of nonuniform frame weights into a structural clustering method entitled shapeGMM. The result of frame-weighted shapeGMM is a high dimensional probability density and generative model for the unbiased system from which we can compute important thermodynamic properties such as relative free energies and configurational entropy. The accuracy of this approach is demonstrated by the quantitative agreement between GMMs computed by Hamiltonian reweighting and direct simulation of a coarse-grained helix model system. Furthermore, the relative free energy computed from a shapeGMM probability density of alanine dipeptide reweighted from a metadynamics simulation quantitatively reproduces the underlying free energy in the basins. Finally, the method identifies hidden structures along the actin globular to filamentous-like structural transition from a metadynamics simulation on a linear discriminant analysis coordinate trained on GMM states, illustrating how structural clustering of biased data can lead to biophysical insight. Combined, these results demonstrate that frame-weighted shapeGMM is a powerful approach to quantifying biomolecular ensembles from biased simulations.

Achieving precise control over gelator alignment and morphology is crucial for crafting tailored materials and supramolecular structures with distinct properties. We successfully aligned the self-assembled micelles formed by a functionalized dipeptide 2NapFF into long 1-D "gel noodles" by cross-linking with divalent metal chlorides. We identify the most effective cross-linker for alignment, enhancing mechanical stability, and imparting functional properties. Our study shows that Group 2 metal ions are particularly suited for creating mechanically robust yet flexible gel noodles because of their ionic and nondirectional bonding with carboxylate groups. In contrast, the covalent nature and high directional bonds of d -block metal ions with carboxylates tend to disrupt the self-assembly of 2NapFF. Furthermore, the 2NapFF-Cu noodles demonstrated selective antibacterial activity, indicating that the potent antibacterial property of the copper(II) ion is preserved within the cross-linked system. By merging insights into molecular alignment, gel extrusion processing, and integrating specific functionalities, we illustrate how the versatility of dipeptide-based gels can be utilized in creating next-generation soft materials.

Several enhanced sampling techniques rely on the definition of collective variables to effectively explore free energy landscapes. The existing variables that describe the progression along a reactive pathway offer an elegant solution but face a number of limitations. In this paper, we address these challenges by introducing a new path-like collective variable called the "deep-locally non-linear-embedding," which is inspired by principles of the locally linear embedding technique and is trained on a reactive trajectory. The variable mimics the ideal reaction coordinate by automatically generating a non-linear combination of features through a differentiable generalized autoencoder that combines a neural network with a continuous k-nearest neighbor selection. Among the key advantages of this method is its capability to automatically choose the metric for searching neighbors and to learn the path from state A to state B without the need to handpick landmarks a priori. We demonstrate the effectiveness of DeepLNE by showing that the progression along the path variable closely approximates the ideal reaction coordinate in toy models, such as the Müller-Brown potential and alanine dipeptide. Then, we use it in the molecular dynamics simulations of an RNA tetraloop, where we highlight its capability to accelerate transitions and estimate the free energy of folding., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Dipeptides of a new structure based on β-triazolalanines and (L)-α-amino acids were synthesized and optimal conditions were developed that ensure both chemical and optical purity of the final products. Molecular docking was carried out and possible intermolecular interactions of dipeptides with potential targets were established. Based on these studies, the analgesic property of chosen dipeptides was studied and it was found that some compounds possess revealed antinociceptive activity in the tail-flick test., (© 2024 Wiley-VCH GmbH.)

Virtual combinatorial libraries are prevalent in drug discovery due to improvements in the prediction of synthetic reactions that can be performed. This has gone hand in hand with the development of virtual screening capabilities to effectively screen the large chemical spaces spanned by exhaustive enumeration of reaction products. In this study, we generated a small-molecule dipeptide mimic library to target proteins binding small peptides. The library was created based on the general idea of peptide synthesis, that is, amino acid mimics were reacted in silico to form the dipeptide mimics, yielding 2,036,819 unique compounds. After docking calculations, two compounds from the library were synthesized and tested against WD repeat-containing protein 5 (WDR5) and histamine receptors H 1 -H 4 to evaluate whether these molecules are viable in assays. The compounds showed the highest potency at the histamine H 3 receptor, with K i values in the two-digit micromolar range., (© 2024 The Authors. Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

The emergence and spread of antimicrobial resistance are global threats. Pseudomonas aeruginosa (P. aeruginosa) is responsible for a substantial proportion of this global health issue because of its intrinsic resistance to many antibiotics due to the impermeability of its outer membrane and its multidrug efflux pump systems. Therefore, therapeutic drugs are limited, and the development of new drugs is extremely challenging. As an alternative approach, we focused on a combinational treatment strategy and found that 5-O-mycaminosyltylonolide (OMT) showed potent antibacterial activity against P. aeruginosa in the presence of an efflux pump inhibitor, phenylalanine-arginine beta-naphthylamide (PAβN). In this report, we prepared a PAβN derivative and compared the potentiation activity of OMT by PAβNs against multidrug-resistant P. aeruginosa clinical isolates., (© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

This work describes the self-assembly behavior of heterochiral, aliphatic dipeptides, l-Leu-d-Xaa (Xaa = Ala, Val, Ile, Leu), in green solvents such as acetonitrile (MeCN) and buffered water at neutral pH. Interestingly, water plays a structuring role because at 1% v/v, it enables dipeptide self-assembly in MeCN to yield organogels, which then undergo transition towards crystals. Other organic solvents and oils were tested for gelation, and metastable gels were formed in tetrahydrofuran, although at high peptide concentration (80 mM). Single-crystal X-ray diffraction revealed the dipeptides' supramolecular packing modes in amphipathic layers, as opposed to water channels reported for the homochiral Leu-Leu, or hydrophobic columns reported for homochiral Leu-Val and Leu-Ile., (© 2023 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

Cells require oligonucleotides and polypeptides with specific, homochiral sequences to perform essential functions, but it is unclear how such oligomers were selected from random sequences at the origin of life. Cells were probably preceded by simple compartments such as fatty acid vesicles, and oligomers that increased the stability, growth, or division of vesicles could have thereby increased in frequency. We therefore tested whether prebiotic peptides alter the stability or growth of vesicles composed of a prebiotic fatty acid. We find that three of 15 dipeptides tested reduce salt-induced flocculation of vesicles. All three contain leucine, and increasing their length increases the efficacy. Also, leucine-leucine but not alanine-alanine increases the size of vesicles grown by multiple additions of micelles. In a molecular simulation, leucine-leucine docks to the membrane, with the side chains inserted into the hydrophobic core of the bilayer, while alanine-alanine fails to dock. Finally, the heterochiral forms of leucine-leucine, at a high concentration, rapidly shrink the vesicles and make them leakier and less stable to high pH than the homochiral forms do. Thus, prebiotic peptide-membrane interactions influence the flocculation, growth, size, leakiness, and pH stability of prebiotic vesicles, with differential effects due to sequence, length, and chirality. These differences could lead to a population of vesicles enriched for peptides with beneficial sequence and chirality, beginning selection for the functional oligomers that underpin life.

Modified cyclic dipeptides represent a widespread class of secondary metabolites with diverse pharmacological activities, including antibacterial, antifungal, and antitumor. Here, we report the structural characterization of the Streptomyces noursei enzyme AlbAB, a cyclodipeptide oxidase (CDO) carrying out α,β-dehydrogenations during the biosynthesis of the antibiotic albonoursin. We show that AlbAB is a megadalton heterooligomeric enzyme filament containing covalently bound flavin mononucleotide cofactors. We highlight that AlbAB filaments consist of alternating dimers of AlbA and AlbB and that enzyme activity is crucially dependent on filament formation. We show that AlbA-AlbB interactions are highly conserved suggesting that other CDO-like enzymes are likely enzyme filaments. As CDOs have been employed in the structural diversification of cyclic dipeptides, our results will be useful for future applications of CDOs in biocatalysis and chemoenzymatic synthesis., (© 2024. The Author(s).)