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Search Results (228)

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Keywords = small molecule fragmentation

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17 pages, 7247 KiB  
Article
Identification of eccDNA in Extracellular Vesicles Derived from Human Dermal Fibroblasts Through Nanopore Sequencing
by Bianca Simonassi-Paiva, Julia Alves Luz, Julia Hellena Ribeiro, Juliano Coelho da Silveira, Camila Azzolin de Souza, Georgios Joannis Pappas Jr, Juliana Lott de Carvalho, Mark Lynch, Robert Pogue and Neil J. Rowan
Int. J. Mol. Sci. 2025, 26(9), 4144; https://doi.org/10.3390/ijms26094144 - 27 Apr 2025
Viewed by 204
Abstract
Extrachromosomal circular DNAs (eccDNAs) are heterogeneous circular DNA molecules derived from genomic DNA, and believed to be involved in intercellular communication and in natural biological processes. Extracellular vesicles (EVs) are membrane-bound particles released from all cells, and have been shown to contain various [...] Read more.
Extrachromosomal circular DNAs (eccDNAs) are heterogeneous circular DNA molecules derived from genomic DNA, and believed to be involved in intercellular communication and in natural biological processes. Extracellular vesicles (EVs) are membrane-bound particles released from all cells, and have been shown to contain various classes of nucleic acids. EVs can play a role in intercellular communication and may be used as biomarkers. This constitutes the first study to demonstrate that EVs derived from healthy human dermal fibroblasts carry eccDNA. eccDNA from EVs and their corresponding donor cells were isolated and sequenced on the Oxford Nanopore MinIon platform, followed by the identification of potential eccDNAs through four different bioinformatic pipelines, namely ecc_Finder, cyrcular-calling, CReSIL, and Flec. Our main findings demonstrate that EVs derived from human dermal fibroblasts carry eccDNA; there is variability in the number of eccDNAs identified in the same sample through different pipelines; and there is variability in the identified eccDNAs across biological replicates. Additionally, eccDNAs characterized in this research had (a) sequences as small as 306 base pairs and as large as 28,958 base pairs across all samples, (b) uneven chromosomal distribution, and (c) an average of 49.7% of the identified eccDNAs harboring gene fragments. Future implications for this novel research include using this framework method to elucidate factors and conditions that may influence the skin aging process and related biogenesis in human dermal cells. Full article
(This article belongs to the Section Molecular Nanoscience)
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11 pages, 3082 KiB  
Article
Scanning Tunneling Microscope Measurement of Proteasome Conductance
by Sepideh Afsari, Eathen Ryan, Brian Ashcroft, Xu Wang and Stuart Lindsay
Biomolecules 2025, 15(4), 496; https://doi.org/10.3390/biom15040496 - 28 Mar 2025
Viewed by 310
Abstract
The proteasome is an enzyme that sequentially degrades peptides into small fragments, so the ability to make electrical measurements of its conformational fluctuations could lead to an electronic readout of the sequence of single peptide molecules. Here, we report scanning tunneling microscope (STM) [...] Read more.
The proteasome is an enzyme that sequentially degrades peptides into small fragments, so the ability to make electrical measurements of its conformational fluctuations could lead to an electronic readout of the sequence of single peptide molecules. Here, we report scanning tunneling microscope (STM) measurements of the conductance of the T. acidophilum 20S proteasome core particle (CP). The wild-type CP did not change conductance significantly as a 4 amino acid peptide substrate was added. Larger peptides were digested by a mutant, CP-Δ12, in which 12 residues were deleted from the N terminus of the alpha chains (opening the central pore). The conductance of this molecule decreased significantly in the presence of a denatured pleiotrophin substrate. Control experiments showed that strong bonding of the protein, both to the substrate electrode and the STM probe, was required for conductivity to be observed. It also appears that substantial penetration of the probe into the protein film is required, a problematic constraint on incorporating the CP into a fixed-gap device for technological applications. Full article
(This article belongs to the Special Issue Single-Molecule Protein Electronics)
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14 pages, 6876 KiB  
Article
Near-Edge X-Ray Absorption Fine-Structure Spectra and Specific Dissociation of Phe-Gly and Gly-Phe
by Tse-Fu Shen, Yu-Ju Chiang, Yi-Shiue Lin, Chen-Lin Liu, Yu-Chiao Wang, Kuan-Yi Chou, Cheng-Cheng Tsai and Wei-Ping Hu
Int. J. Mol. Sci. 2025, 26(6), 2515; https://doi.org/10.3390/ijms26062515 - 11 Mar 2025
Viewed by 625
Abstract
The total-ion-yield (TIY) near-edge X-ray absorption fine-structure (NEXAFS) spectra of two dipeptides were measured and analyzed to identify the excitation sites of core electrons and the corresponding destination molecular orbitals. Peptide molecules were transferred to the gaseous phase using traditional heating and MALDI [...] Read more.
The total-ion-yield (TIY) near-edge X-ray absorption fine-structure (NEXAFS) spectra of two dipeptides were measured and analyzed to identify the excitation sites of core electrons and the corresponding destination molecular orbitals. Peptide molecules were transferred to the gaseous phase using traditional heating and MALDI methods, ensuring that the resulting NEXAFS spectra and fragmentation products were consistent across both approaches. Mass spectra obtained at various excitation energies revealed the branching ratios of products at each energy level, offering insights into specific dissociation phenomena. Notably, variations in excitation energy demonstrated a selective dissociation process, with certain products forming more efficiently. This specificity appears closely linked to dissociations near the peptide bond, where the nodal planes of destination molecular orbitals are located. These findings were validated using both small peptide models and peptoid molecules, highlighting consistent patterns in the dissociation behavior. Full article
(This article belongs to the Section Molecular Informatics)
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17 pages, 3115 KiB  
Article
Fragmentation and Isomerization Pathways of Natural and Synthetic Cannabinoids Studied via Higher Collisional Energy Dissociation Profiles
by Kgato P. Selwe, Ambar S. A. Shaikh, Kelechi O. Uleanya and Caroline E. H. Dessent
Molecules 2025, 30(3), 717; https://doi.org/10.3390/molecules30030717 - 5 Feb 2025
Viewed by 762
Abstract
Cannabinoid molecules are the family of molecules that bind to the cannabinoid receptors (CB1 and CB2) of the human body and cause changes in numerous biological functions including motor coordination, emotion, and pain reception. Cannabinoids occur either naturally in the Cannabis Sativa plant [...] Read more.
Cannabinoid molecules are the family of molecules that bind to the cannabinoid receptors (CB1 and CB2) of the human body and cause changes in numerous biological functions including motor coordination, emotion, and pain reception. Cannabinoids occur either naturally in the Cannabis Sativa plant or can be produced synthetically in the laboratory. The need for accurate analytical methods for analyzing cannabinoid molecules is of considerable current importance due to demands for detecting illegal cannabinoids and for monitoring the manufacture of popular, non-illegal cannabinoid products. Mass spectrometry has been shown to be an optimum technique for identifying cannabinoids. In this work, we perform Higher Collisional Dissociation (HCD) mass spectrometric measurements on an Orbitrap Fusion Tribrid Mass Spectrometer to measure the collision-energy-dependent molecular fragmentation pathways of a group of key cannabinoids and their metabolites (cannabidiol, Δ9-Tetrahydrocannabinol, 11-Hydroxy-Δ9-tetrahydrocannabinol, 11-nor-9-Carboxy-Δ9-tetrahydrocannabinol, cannabidiolic acid, tetrahydrocannabinolic acid), along with two synthetic cannabinoids (JWH-018 and MDMB-FUBINACA). This is the first time that cannabinoid molecules have been studied using energy-resolved HCD methods. We identified a number of common, primary fragmentation pathways, including loss of water, loss of other small neutral molecule units (e.g., butene), and rupture of the central C-C bond that links the aromatic and alkyl ring groups. Quantum chemical calculations are presented to provide insights into preferred protonation sites and to characterize isomerization of protonated open-ring cannabinoids (e.g., [CBDA + H]+) into closed-ring analogues (e.g., [THCA + H]+). A key result to emerge from our study is that energy-resolved HCD measurements are particularly valuable in identifying isomerization, since the isobaric pairs of molecular ions studied here (e.g., [CBDA + H]+ and [THCA + H]+) are associated with identical HCD profiles indicating that isomerization of one structure into the other has occurred during the electrospray–mass spectrometry process. This is an important result as it will have general applicability to other tautomeric ions and thus demonstrates the application of energy-resolved HCD as a tool for identifying tautomerization proclivity. Full article
(This article belongs to the Section Physical Chemistry)
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13 pages, 984 KiB  
Review
Role of tRNA-Derived Fragments in Protozoan Parasite Biology
by Manu Sharma and Upinder Singh
Cells 2025, 14(2), 115; https://doi.org/10.3390/cells14020115 - 14 Jan 2025
Cited by 1 | Viewed by 912
Abstract
tRNA molecules are among the most fundamental and evolutionarily conserved RNA types, primarily facilitating the translation of genetic information from mRNA into proteins. Beyond their canonical role as adaptor molecules during protein synthesis, tRNAs have evolved to perform additional functions. One such non-canonical [...] Read more.
tRNA molecules are among the most fundamental and evolutionarily conserved RNA types, primarily facilitating the translation of genetic information from mRNA into proteins. Beyond their canonical role as adaptor molecules during protein synthesis, tRNAs have evolved to perform additional functions. One such non-canonical role for tRNAs is through the generation of tRNA-derived fragments via specific cleavage processes. These tRNA-derived small RNAs (tsRNAs) are present across all three domains of life, including in protozoan parasites. They are formed through the cleavage of the parent tRNA molecules at different sites, resulting in either tRNA halves or smaller fragments. The precise mechanisms underlying the synthesis of various tRNA-derived fragments, including the specific RNases involved, as well as their distinct functions and roles in parasite physiology, are not yet fully understood and remain an active area of ongoing research. However, their role in modulating gene expression, particularly during stress responses, is becoming increasingly evident. In this context, we discuss recent findings on the roles of tRNA-derived small RNA in various protozoan parasites. Furthermore, we investigate how these tsRNAs either modulate gene expression within the parasite itself or are packaged into extracellular vesicles to alter host gene expression, thereby promoting parasite survival and adaptation. Full article
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22 pages, 2915 KiB  
Article
Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity
by Kostiantyn Shabelnyk, Alina Fominichenko, Oleksii Antypenko, Olexandr Gaponov, Svitlana Koptieva, Svitlana Shyshkina, Oleksii Voskoboinik, Sergiy Okovytyy, Serhii Kovalenko, Valentyn Oksenych and Oleksandr Kamyshnyi
Pharmaceuticals 2025, 18(1), 83; https://doi.org/10.3390/ph18010083 - 11 Jan 2025
Viewed by 1015
Abstract
Background: In the era of resistance, the design and search for new “small” molecules with a narrow spectrum of activity that target a protein or enzyme specific to a certain bacterium with high selectivity and minimal side effects remains an urgent problem of [...] Read more.
Background: In the era of resistance, the design and search for new “small” molecules with a narrow spectrum of activity that target a protein or enzyme specific to a certain bacterium with high selectivity and minimal side effects remains an urgent problem of medicinal chemistry. In this regard, we developed and successfully implemented a strategy for the search for new hybrid molecules, namely, the not broadly known [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines. They can act as “building blocks” and allow for the introduction of certain structural motifs into the desired final products in order to enhance the antistaphylococcal effect. Methods: The “one-pot” synthesis of the latter is based on the conversion of substituted 4-hydrazinoquinazolines or substituted 2-aminobenzonitriles and carboxylic acid derivatives to the target products. The possible molecular mechanism of the synthesized compounds (DNA gyrase inhibitors) was investigated and discussed using molecular docking, and their further study for antistaphylococcal activity was substantiated. Results: A significant part of the obtained compounds showed high antibacterial activity against Staphylococcus aureus (MIC: 10.1–62.4 µM) and 5-bromo-2-(3-(furan-3-yl)-1H-1,2,4-triazol-5-yl)aniline and 5-fluoro-2-(3-(thiophen-3-yl)-1H-1,2,4-triazol-5-yl)aniline, with MICs of 5.2 and 6.1 µM, respectively, approaching the strength of the effect of the reference drug, “Ciprofloxacin” (MIC: 4.7 µM). The conducted SAR and ADME analyses confirm the prospects of the further structural modification of these compounds. The obtained [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antimicrobial activity and deserve further structural modification and detailed study as effective antistaphylococcal agents. The SAR analysis revealed that the presence of a cycloalkyl or electron-rich heterocyclic fragment in the third position of the triazole ring was essential for the antibacterial activity of the obtained compounds. At the same time, the introduction of a methyl group into the aniline moiety led to an enhancement of activity. The introduction of halogen into the aniline fragment has an ambiguous effect on the level of antistaphylococcal activity and depends on the nature of the substituent in the third position. Conclusions: Obtained [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antistaphylococcal activity and deserve for further detailed study as effective antibacterial agents. Full article
(This article belongs to the Section Biopharmaceuticals)
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16 pages, 2423 KiB  
Article
DENV-1 Infection of Macrophages Induces Pyroptosis and Causes Changes in MicroRNA Expression Profiles
by Qinyi Zhang, Sicong Yu, Zhangnv Yang, Xingxing Wang, Jianhua Li, Lingxuan Su, Huijun Zhang, Xiuyu Lou, Haiyan Mao, Yi Sun, Lei Fang, Hao Yan and Yanjun Zhang
Biomedicines 2024, 12(12), 2752; https://doi.org/10.3390/biomedicines12122752 - 30 Nov 2024
Viewed by 1099
Abstract
Background: Dengue virus (DENV) is the most widespread mosquito-borne virus, which can cause dengue fever with mild symptoms, or progress to fatal dengue hemorrhagic fever and dengue shock syndrome. As the main target cells of DENV, macrophages are responsible for the innate immune [...] Read more.
Background: Dengue virus (DENV) is the most widespread mosquito-borne virus, which can cause dengue fever with mild symptoms, or progress to fatal dengue hemorrhagic fever and dengue shock syndrome. As the main target cells of DENV, macrophages are responsible for the innate immune response against the virus. Methods: In this study, we investigated the role of pyroptosis in the pathogenic mechanism of dengue fever by examining the level of pyroptosis in DENV-1-infected macrophages and further screened differentially expressed microRNAs by high-throughput sequencing to predict microRNAs that could affect the pyroptosis of the macrophage. Results: Macrophages infected with DENV-1 were induced with decreased cell viability, decreased release of lactate dehydrogenase and IL-1β, activation of NLRP3 inflammasome and caspase-1, cleavage of GSDMD to produce an N-terminal fragment bound to cell membrane, and finally induced macrophage pyroptosis. MicroRNA expression profiles were obtained by sequencing macrophages from all periods of DENV-1 infection and comparing with the negative control. Sixty-three microRNAs differentially expressed in both the early and later stages of infection were also identified. In particular, miR-223-3p, miR-148a-3p, miR-125a-5p, miR-146a-5p and miR-34a-5p were recognized as small molecules that may be involved in the regulation of inflammation. Conclusions: In summary, this study aimed to understand the pathogenic mechanism of DENV through relevant molecular mechanisms and provide new targets for dengue-specific therapy. Full article
(This article belongs to the Special Issue Pathogenic Mechanism and Biosafety of Pathogenic Microorganisms)
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19 pages, 2205 KiB  
Article
An Ultra-Fast Validated Green UPLC-MS/MS Approach for Assessing Revumenib in Human Liver Microsomes: In Vitro Absorption, Distribution, Metabolism, and Excretion and Metabolic Stability Evaluation
by Mohamed W. Attwa, Ali S. Abdelhameed and Adnan A. Kadi
Medicina 2024, 60(12), 1914; https://doi.org/10.3390/medicina60121914 - 21 Nov 2024
Cited by 3 | Viewed by 1130
Abstract
Background and Objectives: Revumenib (SNDX-5613) is a powerful and specific inhibitor of the menin–KMT2A binding interaction. It is a small molecule that is currently being researched to treat KMT2A-rearranged (KMT2Ar) acute leukemias. Revumenib (RVB) has received Orphan Drug Designation from the US FDA [...] Read more.
Background and Objectives: Revumenib (SNDX-5613) is a powerful and specific inhibitor of the menin–KMT2A binding interaction. It is a small molecule that is currently being researched to treat KMT2A-rearranged (KMT2Ar) acute leukemias. Revumenib (RVB) has received Orphan Drug Designation from the US FDA for treating patients with AML. It has also been granted Fast Track designation by the FDA for treating pediatric and adult patients with R/R acute leukemias that have a KMT2Ar or NPM1 mutation. Materials and Methods: The target of this research was to create a fast, precise, green, and extremely sensitive UPLC-MS/MS technique for the estimation of the RVB level in human liver microsomes (HLMs), employing an ESI source. The validation procedures were carried out in accordance with the bioanalytical technique validation requirements established by the US Food and Drug Administration that involve linearity, selectivity, precision, accuracy, stability, matrix effect, and extraction recovery. The outcome data of the validation features of the UPLC-MS/MS approach were acceptable according to FDA guidelines. RVB parent ions were formed in the positive ESI source and its two fragment ions were estimated employing multiple reaction monitoring (MRM) mode. The separation of RVB and encorafenib was achieved using a C8 column (2.1 mm, 50 mm, and 3.5 µm) and isocratic mobile phase. Results: The RVB calibration curve linearity ranged from 1 to 3000 ng/mL (y = 0.6515x − 0.5459 and R2 = 0.9945). The inter-day precision and accuracy spanned from −0.23% to 11.33%, while the intra-day precision and accuracy spanned from −0.88% to 11.67%, verifying the reproducibility of the UPLC-MS/MS analytical technique. The sensitivity of the developed methodology demonstrated its capability to quantify RVB levels at an LOQ of 0.96 ng/mL. The AGREE score was 0.77, confirming the greenness of the current method. The low in vitro t1/2 (14.93 min) and high intrinsic clearance (54.31 mL/min/kg) of RVB revealed that RVB shares similarities with medications that have a high extraction ratio. Conclusions: The present LC-MS/MS approach is considered the first analytical approach with the application of metabolic stability assessment for RVB estimation in HLMs. These methods are essential for advancing the development of new pharmaceuticals, particularly in enhancing metabolic stability. Full article
(This article belongs to the Special Issue Acute Myeloid Leukemia: Update on Diagnosis, Therapy, and Monitoring)
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19 pages, 11582 KiB  
Article
Small Molecule Inhibitor of Protein Kinase C DeltaI (PKCδI) Decreases Inflammatory Pathways and Gene Expression and Improves Metabolic Function in Diet-Induced Obese Mouse Model
by Brenna Osborne, Rekha S. Patel, Meredith Krause-Hauch, Ashley Lui, Gitanjali Vidyarthi and Niketa A. Patel
Biology 2024, 13(11), 943; https://doi.org/10.3390/biology13110943 - 18 Nov 2024
Cited by 1 | Viewed by 1364
Abstract
Obesity promotes metabolic diseases such as type 2 diabetes and cardiovascular disease. PKCδI is a serine/threonine kinase which regulates cell growth, differentiation, and survival. Caspase-3 cleavage of PKCδI releases the C-terminal catalytic fragment (PKCδI_C), which promotes inflammation and apoptosis. We previously demonstrated an [...] Read more.
Obesity promotes metabolic diseases such as type 2 diabetes and cardiovascular disease. PKCδI is a serine/threonine kinase which regulates cell growth, differentiation, and survival. Caspase-3 cleavage of PKCδI releases the C-terminal catalytic fragment (PKCδI_C), which promotes inflammation and apoptosis. We previously demonstrated an increase in PKCδI_C in human obese adipose tissue (AT) and adipocytes. Subsequently, we designed a small molecule drug called NP627 and demonstrated that NP627 specifically inhibited the release of PKCδI_C in vitro. Here, we evaluate the in vivo safety and efficacy of NP627 in a diet-induced obese (DIO) mouse model. The results demonstrate that NP627 treatment in DIO mice increased glucose uptake and inhibited the cleavage of PKCδI_C in the AT as well as in the kidney, spleen, and liver. Next, RNAseq analysis was performed on the AT from the NP627-treated DIO mice. The results show increases in ADIPOQ and CIDEC, upregulation of AMPK, PI3K-AKT, and insulin signaling pathways, while inflammatory pathways were decreased post-NP627 administration. Further, levels of lncRNAs associated with metabolic pathways were affected by NP627 treatment. In conclusion, the study demonstrates that NP627, a small-molecule inhibitor of PKCδI activity, is not toxic and that it improves the metabolic function of DIO mice in vivo. Full article
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16 pages, 2277 KiB  
Review
Drug Discovery in the Age of Artificial Intelligence: Transformative Target-Based Approaches
by Akshata Yashwant Patne, Sai Madhav Dhulipala, William Lawless, Satya Prakash, Shyam S. Mohapatra and Subhra Mohapatra
Int. J. Mol. Sci. 2024, 25(22), 12233; https://doi.org/10.3390/ijms252212233 - 14 Nov 2024
Cited by 3 | Viewed by 3083
Abstract
The complexities inherent in drug development are multi-faceted and often hamper accuracy, speed and efficiency, thereby limiting success. This review explores how recent developments in machine learning (ML) are significantly impacting target-based drug discovery, particularly in small-molecule approaches. The Simplified Molecular Input Line [...] Read more.
The complexities inherent in drug development are multi-faceted and often hamper accuracy, speed and efficiency, thereby limiting success. This review explores how recent developments in machine learning (ML) are significantly impacting target-based drug discovery, particularly in small-molecule approaches. The Simplified Molecular Input Line Entry System (SMILES), which translates a chemical compound’s three-dimensional structure into a string of symbols, is now widely used in drug design, mining, and repurposing. Utilizing ML and natural language processing techniques, SMILES has revolutionized lead identification, high-throughput screening and virtual screening. ML models enhance the accuracy of predicting binding affinity and selectivity, reducing the need for extensive experimental screening. Additionally, deep learning, with its strengths in analyzing spatial and sequential data through convolutional neural networks (CNNs) and recurrent neural networks (RNNs), shows promise for virtual screening, target identification, and de novo drug design. Fragment-based approaches also benefit from ML algorithms and techniques like generative adversarial networks (GANs), which predict fragment properties and binding affinities, aiding in hit selection and design optimization. Structure-based drug design, which relies on high-resolution protein structures, leverages ML models for accurate predictions of binding interactions. While challenges such as interpretability and data quality remain, ML’s transformative impact accelerates target-based drug discovery, increasing efficiency and innovation. Its potential to deliver new and improved treatments for various diseases is significant. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery, 2nd Edition)
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19 pages, 8146 KiB  
Article
Computational Insights into Acrylamide Fragment Inhibition of SARS-CoV-2 Main Protease
by Ping Chen, Liyuan Wu, Bo Qin, Haodong Yao, Deting Xu, Sheng Cui and Lina Zhao
Curr. Issues Mol. Biol. 2024, 46(11), 12847-12865; https://doi.org/10.3390/cimb46110765 - 12 Nov 2024
Viewed by 1202
Abstract
The pathogen of COVID-19, SARS-CoV-2, has caused a severe global health crisis. So far, while COVID-19 has been suppressed, the continuous evolution of SARS-CoV-2 variants has reduced the effectiveness of vaccines such as mRNA-1273 and drugs such as Remdesivir. To uphold the effectiveness [...] Read more.
The pathogen of COVID-19, SARS-CoV-2, has caused a severe global health crisis. So far, while COVID-19 has been suppressed, the continuous evolution of SARS-CoV-2 variants has reduced the effectiveness of vaccines such as mRNA-1273 and drugs such as Remdesivir. To uphold the effectiveness of vaccines and drugs prior to potential coronavirus outbreaks, it is necessary to explore the underlying mechanisms between biomolecules and nanodrugs. The experimental study reported that acrylamide fragments covalently attached to Cys145, the main protease enzyme (Mpro) of SARS-CoV-2, and occupied the substrate binding pocket, thereby disrupting protease dimerization. However, the potential mechanism linking them is unclear. The purpose of this work is to complement and validate experimental results, as well as to facilitate the study of novel antiviral drugs. Based on our experimental studies, we identified two acrylamide fragments and constructed corresponding protein-ligand complex models. Subsequently, we performed molecular dynamics (MD) simulations to unveil the crucial interaction mechanisms between these nanodrugs and SARS-CoV-2 Mpro. This approach allowed the capture of various binding conformations of the fragments on both monomeric and dimeric Mpro, revealing significant conformational dissociation between the catalytic and helix domains, which indicates the presence of allosteric targets. Notably, Compound 5 destabilizes Mpro dimerization and acts as an effective inhibitor by specifically targeting the active site, resulting in enhanced inhibitory effects. Consequently, these fragments can modulate Mpro’s conformational equilibrium among extended monomeric, compact, and dimeric forms, shedding light on the potential of these small molecules as novel inhibitors against coronaviruses. Overall, this research contributes to a broader understanding of drug development and fragment-based approaches in antiviral covalent therapeutics. Full article
(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)
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13 pages, 3422 KiB  
Article
The Inhibition of Serum Amyloid A Protein Aggregation by a Five-Residue Peptidomimetic: Structural and Morphological Insights
by Julia Witkowska, Sandra Skibiszewska, Paweł Wityk, Marcel Pilarski and Elżbieta Jankowska
Molecules 2024, 29(21), 5165; https://doi.org/10.3390/molecules29215165 - 31 Oct 2024
Viewed by 971
Abstract
Serum amyloid A (SAA) is a small protein consisting of 104 residues and, under physiological conditions, exists mainly in hexameric form. It belongs to the positive acute-phase proteins, which means that its plasma concentration increases rapidly in response to injury, inflammation, and infection. [...] Read more.
Serum amyloid A (SAA) is a small protein consisting of 104 residues and, under physiological conditions, exists mainly in hexameric form. It belongs to the positive acute-phase proteins, which means that its plasma concentration increases rapidly in response to injury, inflammation, and infection. The accumulation of SAA molecules promotes the formation of amyloid aggregates, which deposit extracellularly in many organs, causing their dysfunction. In our previous work, we successfully designed a peptidomimetic that inhibited the aggregation of amyloidogenic SAA fragments. In the present paper, we show how the same inhibitor, named saa3Dip, affects the oligomerization and aggregation processes of MetSAA1.1 protein. The thioflavin T assay showed that saa3Dip inhibited its fibrillization. The measurement of the internal fluorophore fluorescence (Trp) showed differences that occurred in the tertiary structure of MetSAA1.1 in the presence of the inhibitor, which was also confirmed by CD spectra in the aromatic range. FTIR results suggested that saa3Dip could stabilize some fragments of the native structure of MetSAA1.1, which was confirmed by determining the melting temperature (Tm) of the protein–inhibitor complex. AFM images demonstrated that the presence of saa3Dip prevented the formation of large SAA aggregates. Our results suggest that saa3Dip stabilizes the native conformation of MetSAA1.1. Full article
(This article belongs to the Special Issue The Role of Peptides and Peptidomimetics in Drug Discovery)
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20 pages, 4065 KiB  
Article
Solid-State Structures and Properties of Lignin Hydrogenolysis Oil Compounds: Shedding a Unique Light on Lignin Valorization
by Oliver J. Driscoll, Kristof Van Hecke, Christophe M. L. Vande Velde, Frank Blockhuys, Maarten Rubens, Tatsuhiro Kuwaba, Daniel J. van de Pas, Walter Eevers, Richard Vendamme and Elias Feghali
Int. J. Mol. Sci. 2024, 25(19), 10810; https://doi.org/10.3390/ijms251910810 - 8 Oct 2024
Viewed by 1398
Abstract
This article explores the important, and yet often overlooked, solid-state structures of selected bioaromatic compounds commonly found in lignin hydrogenolysis oil, a renewable bio-oil that holds great promise to substitute fossil-based aromatic molecules in a wide range of chemical and material industrial applications. [...] Read more.
This article explores the important, and yet often overlooked, solid-state structures of selected bioaromatic compounds commonly found in lignin hydrogenolysis oil, a renewable bio-oil that holds great promise to substitute fossil-based aromatic molecules in a wide range of chemical and material industrial applications. At first, single-crystal X-ray diffraction (SCXRD) was applied to the lignin model compounds, dihydroconiferyl alcohol, propyl guaiacol, and eugenol dimers, in order to elucidate the fundamental molecular interactions present in such small lignin-derived polyols. Then, considering the potential use of these lignin-derived molecules as building blocks for polymer applications, structural analysis was also performed for two chemically modified model compounds, i.e., the methylene-bridging propyl-guaiacol dimer and propyl guaiacol and eugenol glycidyl ethers, which can be used as precursors in phenolic and epoxy resins, respectively, thus providing additional information on how the molecular packing is altered following chemical modifications. In addition to the expected H-bonding interactions, other interactions such as π–π stacking and C–H∙∙∙π were observed. This resulted in unexpected trends in the tendencies towards the crystallization of lignin compounds. This was further explored with the aid of DSC analysis and CLP intermolecular energy calculations, where the relationship between the major interactions observed in all the SCXRD solid-state structures and their physico-chemical properties were evaluated alongside other non-crystallizable lignin model compounds. Beyond lignin model compounds, our findings could also provide important insights into the solid-state structure and the molecular organization of more complex lignin fragments, paving the way to the more efficient design of lignin-based materials with improved properties for industrial applications or improving downstream processing of lignin oils in biorefining processes, such as in enhancing the separation and isolation of specific bioaromatic compounds). Full article
(This article belongs to the Special Issue Valorization of Lignocellulosic Biomass)
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18 pages, 2822 KiB  
Article
Effect of Cyclodextrins Formulated in Liposomes and Gold and Selenium Nanoparticles on siRNA Stability in Cell Culture Medium
by Betzaida Castillo Cruz, Sandra Chinapen Barletta, Bryan G. Ortiz Muñoz, Adriana S. Benitez-Reyes, Omar A. Amalbert Perez, Alexander C. Cardona Amador, Pablo E. Vivas-Mejia and Gabriel L. Barletta
Pharmaceuticals 2024, 17(10), 1344; https://doi.org/10.3390/ph17101344 - 8 Oct 2024
Viewed by 1237
Abstract
Background: Encapsulation of siRNA fragments inside liposome vesicles has emerged as an effective method for delivering siRNAs in vitro and in vivo. However, the liposome’s fluid-phospholipid bilayer of liposomes allows siRNA fragments to diffuse out of the liposome, decreasing the dose concentration and [...] Read more.
Background: Encapsulation of siRNA fragments inside liposome vesicles has emerged as an effective method for delivering siRNAs in vitro and in vivo. However, the liposome’s fluid-phospholipid bilayer of liposomes allows siRNA fragments to diffuse out of the liposome, decreasing the dose concentration and therefore the effectiveness of the carrier. We have previously reported that β-cyclodextrins formulated in liposomes help increase the stability of siRNAs in cell culture medium. Here, we continued that study to include α, γ, methyl-β-cyclodextrins and β-cyclodextrin-modified gold and selenium nanoparticles. Methods: We used Isothermal Titration Calorimetry to study the binding thermodynamics of siRNAs to the cyclodextrin-modified nanoparticles and to screen for the best adamantane derivative to modify the siRNA fragments, and we used gel electrophoresis to study the stabilization effect of siRNA by cyclodextrins and the nanoparticles. Results: We found that only β- and methyl-β-cyclodextrins increased siRNA serum stability. Cyclodextrin-modified selenium nanoparticles also stabilize siRNA fragments in serum, and siRNAs chemically modified with an adamantane moiety (which forms inclusion complexes with the cyclodextrin-modified-nanoparticles) show a strong stabilization effect. Conclusions: β-cyclodextrins are good additives to stabilize siRNA in cell culture medium, and the thermodynamic data we generated of the interaction between cyclodextrins and adamantane analogs (widely used in drug delivery studies), should serve as a guide for future studies where cyclodextrins are sought for the delivery and solvation of small organic molecules. Full article
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13 pages, 1960 KiB  
Article
N-Terminal Fragments of TDP-43—In Vitro Analysis and Implication in the Pathophysiology of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
by Anna A. Chami, Léa Bedja-Iacona, Elodie Richard, Debora Lanznaster, Sylviane Marouillat, Charlotte Veyrat-Durebex, Christian R. Andres, Philippe Corcia, Hélène Blasco and Patrick Vourc’h
Genes 2024, 15(9), 1157; https://doi.org/10.3390/genes15091157 - 1 Sep 2024
Cited by 1 | Viewed by 1662
Abstract
Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage [...] Read more.
Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage products of TDP-43 (CTFs), but few have focused on the N-terminal products (NTFs), yet several works and their protein domain composition support the involvement of NTFs in pathophysiology. In the present study, we expressed six NTFs of TDP-43, normally generated in vivo by proteases or following the presence of pathogenic genetic truncating variants, in HEK-293T cells. The N-terminal domain (NTD) alone was not sufficient to produce aggregates. Fragments containing the NTD and all or part of the RRM1 domain produced nuclear aggregates without affecting cell viability. Only large fragments also containing the RRM2 domain, with or without the glycine-rich domain, produced cytoplasmic aggregates. Of these, only NTFs containing even a very short portion of the glycine-rich domain caused a reduction in cell viability. Our results provide insights into the involvement of different TDP-43 domains in the formation of nuclear or cytoplasmic aggregates and support the idea that work on the development of therapeutic molecules targeting TDP-43 must also take into account NTFs and, in particular, those containing even a small part of the glycine-rich domain. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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