The Art of Finding the Right Drug Target: Emerging Methods and Strategies

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(5), P. 896 - 914

Published: June 12, 2024

Drug targets are specific molecules in biological tissues and body fluids that interact with drugs. target discovery is a key component of drug essential for the development new drugs areas such as cancer therapy precision medicine. Traditional in vitro or vivo methods time-consuming labour-intensive, limiting pace discovery. With modern methods, application various emerging technologies have greatly improved efficiency discovery, shortened cycle time reduced cost. This review provides comprehensive overview strategies, including computer-assisted approaches, affinity response stability, multiomics analysis, gene editing, NMD, discusses effectiveness limitations well their real cases. Through above related contents, general novel disease treatment strategies will be provided, theoretical basis provided those who engaged pharmaceutical science research. Significance Statement Target-based has been main approach to industry past three decades. based on or validation costly, Therefore, selection process crucial.

Language: Английский

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Targeted deaminase‐free T‐to‐G and C‐to‐K base editing in rice by fused human uracil DNA glycosylase variants

Plant Biotechnology Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Base editors (BEs), a groundbreaking class of genome editing tools, enable precise single-nucleotide alterations at target genomic sites, leading to mutations that either disable or enhance gene functions, thus significantly advancing plant functional genomics research and crop enhancement (Li et al., 2023). In plants, significant advancements have been made in DNA base can directly modify adenine (A), cytosine (C) guanine (G) 2018; Zong 2017). Nevertheless, direct editor for thymine (T) remains elusive. Recently, two innovative deaminase-free glycosylase-based were developed: the gTBE T (T-to-S conversion, S = G C) gCBE C (C-to-G), enabling orthogonal modifications mammalian cells (Figure 1a; Tong 2024). These utilized fusion Cas9 nickase (nCas9) with engineered variants human uracil glycosylase (UNG), allowing excision generate apurinic/apyrimidinic (AP) sites. However, such has not developed plants date. this study, we (pTGBE) (pCKBE, K T) rice, marking substantial step forward expanding genetic manipulation capabilities plants. To establish pTSBE fused rice-codon-optimized variant UNG2Δ88-Y156A/A214T/Q259A/Y284D (mhUNGv3) (Tong 2024) nCas9 32-amino-acid linker. A bipartite nuclear localization signal peptide was UNG increase entry efficiency, resulting construct 1b). We chose ten endogenous sites targeting five genes rice test activities windows. total 400 T0 stable edited obtained Hi-TOM results showed T-to-S conversion transgenic up 78.05% efficiency 1c), but essentially no 1.85% all S1a–c). found also induced insertions deletions (InDels) frequencies ranging from 20.00% 75.32% 1c). Notably, proportion T-to-G edits (up 78.05%, averaging 39.21%) products 13.38-fold higher on average than T-to-C 3.70%, 2.93%). The is predominant type generated, purity exceeding 80% S1d), showing quite different pattern cells. cells, gTBEv3 exhibited activity efficiencies 27.26% 18.75% T-to-C, respectively Thus, designated BE as pTGBE better reflect its characteristics Furthermore, editable range positions T2–T12, T14 T18, optimal window T3–T5 highest T3 (PAM position 21–23) 1d). contrast, typically produced transversions T2-T11 T5 events included homozygous, heterozygous, biallelic chimeric-edited alleles (Table S3; Figure Homozygous conversions observed 60.00% (6/10) sgRNA maximum 30.77% (4/13) OsNRT1.1B-SG3 site, while heterozygous reached 27.78% (15/54) OsARF24-SG2 site. Phytoene desaturase (PDS) key enzyme involved carotenoid biosynthesis, possessing crucial single-domain (amino acids 106–556). #6 underwent homozygous via OsPDS-SG2, alteration Leucine amino acid 114 Valine, albino phenotype white stripes leaves S3). further explored potential application modulating expression through alternative splicing (AS). As pre-mRNA transcripts undergo processing, AS lead intron retention (IR), 5′ splicing, 3′ exon skipping, offering patterns (Liu both donor (SD) site complementary strand acceptor (SA) harbour T. illustrate application, designed sgRNAs specifically SD SA OsARF24 S4). identified mutant #45 desired within splice 1, which targeted by OsARF24-SG1. performed RT-PCR using primer 1 reverse 3. 240 bp fragment generated wild-type (WT) whereas 319 amplified 1f,g). Sequencing revealed retained, completely prevented production normal isoform 1h). Additionally, 12 mutants 7 will produce lines T1 identifying isoforms Overall, our demonstrate program mutating mature transcripts. explore fusing UNG2Δ88-K184A/N213D/A214V (mhUNGv2) evaluating eight three sequencing 255 caused highly efficient 26.09% 61.11%, including C-to-G 58.33% well C-to-T 40.91%, A, examined S2a–c). percentage C-to-G/T almost exceeded 85%, there very few C-to-A detected S2d). Hence, pCKBE. pCKBE C2-C7, C9-C11, C13 C15-C16 1e), InDel 13.04% 72.22% 8.51%), 22.58%), 50.00%) chimeric 22.58%) 1c; Table evaluate specificity lines, selected off-target based predictions Cas-OFFinder (http://www.rgenome.net/cas-offinder/) targets. Minimal effects observed. Only one OsNRT1.1B-SG3-OFF1 OsLCY-SG3-OFF1 detectable S5). novel excised an producing lines. new C-to-K transversion events. greatly broadened scope breaking narrow window, increasing opportunity obtain strategy research. By utilizing edit (AS) providing approach patterns. InDels compared well-developed pABEs pCBEs. pCBEs facilitate repair following deamination reaction. pCKBE, AYBE CGBE, enabled after generation AP are likely double-stranded breaks during these studies suicide HMCES could reduce byproducts shielding safeguarding CGBE TSBE (He 2024; Huang addition, introducing Gam proteins, bind ends DSBs prevent their degradation, reduced (Komor summary, diverse base-editing toolbox. combining other previously reported editors, types be achieved especially future 1i). This study supported National Natural Science Foundation China (32188102 J.-K.Z.) CAAS Nanfan Research Institute, Chinese Academy Agricultural Sciences (YBXM2424 M.L.). authors declare competing interests. M.L. J.-K.Z. research; Y.W., X.W., H.W., Y.H. Y.W. experiments; C.Z., X.W. transformation; analysed data; wrote manuscript. data supports findings available supplementary material article. Figures S1-S5 Supplementary figures. Tables tables. Please note: publisher responsible content functionality any supporting information supplied authors. Any queries (other missing content) should directed corresponding author

Language: Английский

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Adaptation of High-Altitude Plants to Plateau Abiotic Stresses: A Case Study of the Qinghai-Tibet Plateau

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2292 - 2292

Published: March 4, 2025

High-altitude regions offer outstanding opportunities for investigating the impacts of combined abiotic stresses on plant physiological processes given their significant differences in terms ecological environment high-elevation areas, low anthropogenic disturbance, and obvious distribution characteristics plants along altitudinal gradients. Therefore, high-altitude areas can be used as good targets exploring adaptations to stress under extreme conditions. Plants that thrive environments such Qinghai-Tibet Plateau endure stresses, including temperatures, high UV radiation, nutrient-poor soils. This study explores adaptation mechanisms via phenotypic variation analyses multiomics approaches. Key findings highlight traits increased photosynthetic efficiency, robust antioxidant systems, morphological modifications tailored These insights advance our understanding evolution harsh inform strategies increase resistance crops.

Language: Английский

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The ameliorating effects of cinnamic acid-based nanocomposite against salt stress in peppermint

Environmental Science and Pollution Research, Journal Year: 2024, Volume and Issue: 31(32), P. 45055 - 45073

Published: July 3, 2024

Language: Английский

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Deciphering the roles of bacterial and fungal communities in the formation and quality of agarwood

Stress Biology, Journal Year: 2024, Volume and Issue: 4(1)

Published: Sept. 20, 2024

Aquilaria sinensis is a significant resin-producing plant worldwide that crucial for agarwood production. Agarwood has different qualities depending on the method with which it formed, and microbial community structures are present during these methods also diverse. Furthermore, communities of plants play roles in determining their health productivity. While previous studies have investigated impact microorganisms formation, they lack comprehensiveness, particularly regarding properties throughout entire process from seedling to adult incense formation. We collected roots, stems, leaves, flowers, fruits other tissues seedlings, healthy agarwood-producing address this gap assess dominant bacterial species A. at growth stages impacts The bacteria fungi were classified counted perspectives. samples sequenced using Illumina sequencing platform, sequence analyses annotations performed range bioinformatics tools compositions. An additional comparison was conducted diversity differences. This research revealed Listeria, Kurtzmanomyces, Ascotaiwania, Acinetobacter, Sphingobium, Fonsecaea, Acrocalymma, Allorhizobium, Bacillus, Pseudomonas, Peethambara, Debaryomyces potentially associated formation agarwood. Overall, data provided article help us understand important played by sinensis, will support theoretical basis large-scale cultivation provide further applications production beyond.

Language: Английский

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Reading m⁶A marks in mRNA: A potent mechanism of gene regulation in plants

Journal of Integrative Plant Biology, Journal Year: 2024, Volume and Issue: 66(12), P. 2586 - 2599

Published: Oct. 4, 2024

ABSTRACT Modifications to RNA have recently been recognized as a pivotal regulator of gene expression in living organisms. More than 170 chemical modifications identified RNAs, with N 6 ‐methyladenosine (m A) being the most abundant modification eukaryotic mRNAs. The addition and removal m A marks are catalyzed by methyltransferases (referred “writers”) demethylases “erasers”), respectively. In addition, mRNAs interpreted A‐binding proteins “readers”), which regulate fate mRNAs, including stability, splicing, transport, translation. Therefore, exploring mechanism underlying reader‐mediated modulation metabolism is essential for much deeper understanding epigenetic role plants. Recent discoveries improved our functions readers plant growth development, stress response, disease resistance. This review highlights latest developments reader research, emphasizing diverse RNA‐binding domains crucial function biological cellular roles response developmental environmental signals. Moreover, we propose discuss potential future research directions challenges identifying novel elucidating mechanistic

Language: Английский

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Unraveling the Intricacies of Powdery Mildew: Insights into Colonization, Plant Defense Mechanisms, and Future Strategies

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3513 - 3513

Published: April 9, 2025

Powdery mildew, a debilitating phytopathogen caused by biotrophic fungi within the order Erysiphales, endangers crop yields and global food security. Although traditional approaches have largely emphasized resistant cultivar development chemical control, novel strategies are necessary to counter advent of challenges, such as pathogen adaptation climate change. This review fully discusses three principal areas effector functions, e.g., reactive oxygen species (ROS)-suppressive activity CSEP087, host susceptibility factors, like vesicle trafficking regulated Mildew Locus O (MLO). It also briefly mentions transcriptional regulation resistance genes mediated WRKY75 NAC transcription post-transcriptional via alternative splicing (As). In addition, this discussion intricate interactions among powdery plants, symbiotic microbiomes thereof, highlighting mechanism through which mildew infections disrupt foliar microbiota balance. Lastly, we present new biocontrol approach that entails synergistic microbial consortia, combinations Bacillus Trichoderma, induce plant immunity while minimizing fungicide dependency. Through study combining knowledge molecular pathogenesis with ecological resilience, research offers useful insights towards climate-smart sustainable disease-management in context microbiome engineering.

Language: Английский

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The m7G methylation modification: An emerging player of cardiovascular diseases

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 309, P. 142940 - 142940

Published: April 8, 2025

Language: Английский

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A Comprehensive Analysis of the Alternative Splicing Co-Factor U2AF65B Gene Family Reveals Its Role in Stress Responses and Root Development

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3901 - 3901

Published: April 20, 2025

U2AF65, a 65 kDa splicing co-factor, promotes spliceosome assembly. Although its role in alternative (AS) is known, the function of U2AF65B (the large subunit U2AF65) remains unclear. Therefore, we systematically identified and analyzed gene family across 36 plant species, revealing 103 putative members with conserved structures functions. Phylogenetic analysis divided genes into two clades five subgroups, indicating evolutionary divergence. Gene structure motif analyses showed that most have complex shared similar motifs. Homology modeling amino acid conservation revealed significant sequences, particularly Groups D E. Cis-acting element indicated respond to various stimuli, supported by expression under different stress conditions. Subcellular localization predictions proteins primarily localize nucleus cytoplasm. Alternative profile AS frequency likely varies between species. Functional AtU2AF65B mutant Arabidopsis loss enhances root elongation attenuates ABA-dependent germination suppression, negatively regulated seedling growth development. These findings provide insights history, molecular mechanisms, functional roles plants.

Language: Английский

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Synthetic biology and metabolic engineering strategies in identifying and producing plant natural products; with emphasis on the CRISPR/Cas systems

Industrial Crops and Products, Journal Year: 2025, Volume and Issue: 230, P. 121060 - 121060

Published: April 23, 2025

Language: Английский

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