Target For Design Research Articles

The French Medicinal Chemistry Society-SCT, an Historical Member of EFMC.

The French Society of Medicinal Chemistry or " Société de Chimie Thérapeutique " (SCT) was founded in 1966. Since its inception, its mission has been to promote knowledge in the main fields of pharmaceutical research and development, in particular the research and validation of biological targets of therapeutic interest, the screening, design and optimization of drug candidates, chemical biology, medicinal chemistry, pharmacokinetics, metabolism and toxicity. Since 1964, the Society has organized an annual international congress (RICT), and later thematic days for young researchers and workshops on specific topics. The SCT is also a member of the European Federation for Medicinal Chemistry (EFMC) and organized the International Symposium on Medicinal Chemistry (ISMC) in Nice in 2022. Several new trends can be identified in the activities of the SCT, such as the organization of regular webinars, but also the recent creation of the Young MedChem Forum, as well as the distribution of a newsletter reporting scientific achievements in the French community and abroad, and an improved presence on social networks. These trends are in line with the current changes in the field in terms of scientific progress, means of communication in the community and with the public and inclusiveness.

The molecular basis of Human FN3K mediated phosphorylation of glycated substrate.

Glycation, a non-enzymatic post-translational modification occurring on proteins, can be actively reversed via site-specific phosphorylation of the fructose-lysine moiety by FN3K kinase, to impact the cellular function of target protein. A regulatory axis between FN3K and glycated protein targets has been associated with conditions like diabetes and cancer. However the molecular basis of this relationship has not been explored so far. Here, we determined a series of crystal structures of HsFN3K in apo-state, and in complex with different nucleotide analogs together with a sugar substrate mimic to reveal the features important for its kinase activity and substrate recognition. Additionally, the dynamics in sugar substrate binding during the kinase catalytic cycle provide important mechanistic insights into HsFN3K function. Our structural work provides the molecular basis for rationale small molecule design targeting FN3K.

Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease.

The emergence of drug-resistance-inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 14 positions within the ligand-binding residues of HCV NS3/4A, including H57R and S139P within the catalytic triad. We then modelled each mutational variant for pharmacophore-based virtual screening (PBVS) followed by covalent docking towards identifying a potential covalent inhibitor, i.e., cpd-217. The binding stability of cpd-217 was then supported by molecular dynamic simulation followed by MM/GBSA binding free energy calculation. The free energy decomposition analysis indicated that the resistant mutants alter the HCV NS3/4A-ligand interaction, resulting in unbalanced energy distribution within the binding site, leading to drug resistance. Cpd-217 was identified as interacting with all NS3/4A G3 variants with significant covalent docking scores. In conclusion, cpd-217 emerges as a potential inhibitor of HCV NS3/4A G3 variants that warrants further in vitro and in vivo studies. This study provides a theoretical foundation for drug design and development targeting HCV G3 NS3/4A.

RNA splicing as a biomarker and phenotypic driver of meningioma DNA methylation groups.

Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology. This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines. We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design. RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.

Dual detection of Bupleurum scorzonerifolium Willd. and Bupleurum chinense DC. using proofman–LMTIA method

A new rapid dual detection method was established to distinguish Bupleurum scorzonerifolium Willd. (BS) and Bupleurum chinense DC. (BC) simultaneously using the proofreading enzyme-mediated probe cleavage coupled with ladder-shape melting temperature isothermal amplification (proofman–LMTIA). The internal transcribed spacer (ITS) sequences of BS and BC were selected as targets for designs of proofman–LMTIA primers and proofman fluorescence probes labeled with FAM or JOE. The reaction temperature optimization, repeatability and reliability assessment, specificity assessment and sensitivity assessment of the proofman–LMTIA performed for dual detection of BS and BC and its application. The results showed that the optimal reaction temperature of the proofman–LMTIA method was at 63℃, which had strongly specificity, repeatability and reliability, as well as sensitivity, and the detection was completed within 20 min with a detection sensitivity of 1 pg/μL. The proofman–LMTIA method realized dual rapid detection of BS and BC, which showed a strong practical value. The 4 kinds were BC, 1 kind was BS, and 2 kinds were counterfeit in the detection of 7 kinds of BS or BC samples from different habitats. Our study successfully established a new approach for dual rapid detection of BS and BC using the proofman–LMTIA, which will provide an effective technique or method for the authenticity detection of authentic Chinese medicinal materials and present a very important practical significance.Graphical

The Assessment of Knowledge, Attitude, and Practice of Paracetamol and Ibuprofen Administration Among Saudi Parents in the Makkah Region.

Introduction Paracetamol and ibuprofen, widely used for pediatric fever and pain, are safe when administered correctly. However, the caregiver's lack of understanding poses risks such as overdose. Addressing knowledge gaps is crucial due to reported variations in over-the-counter medication practices. "Fever phobia" underscores parental anxiety, stressing the ongoing need for research in this healthcare domain. Methodology This is a descriptive cross-sectional design targeting Saudi parents and caregivers from the Makkah regionwho have children aged 0-10 years. Data was collected via a self-administered validated online questionnaire in the Arabic language using a convenient sampling technique. The data was cleaned in Excel and analyzed using SPSS version 29 (IBM Inc., Armonk, New York). Results Our study included 449 parents and caregivers in the Makkah Region, of whom 337 (75.1%) were female, 179 (39.9%) were aged 18-29, and 425 (94.7%) were Saudi nationals. Knowledge assessment revealed gaps; e.g., only 86 (26.6%) identified baby weight as a dosage factor. Attitudes varied, with 152 (47.1%) associating paracetamol/ibuprofen with liver harm. Logistic regression showed no significant predictors for high-level knowledge, positive attitudes, or good practices, except for gender-influencing good practices (p=0.035, aOR=1.839). Significantly, males exhibited better practices regarding using of paracetamol. Conclusion Our study highlights knowledge gaps among parents and caregivers in the Makkah Region regarding pediatric fever management with paracetamol and ibuprofen. Attitudes varied, and gender significantly influenced good practices, with males demonstrating better adherence to the proper practice of managing children using paracetamol and ibuprofen.

Viewpoint of multi-omics potential in tuberculosis research: identifying biomarkers for biomanufacturing of efficient control tools

Tuberculosis (TB), caused by Mycobacterium tuberculosis complex (MTBC), remains a global health burden, claiming millions of lives annually. Despite the availability of a vaccine (the Bacillus Calmette-Guérin; BCG), diagnostics (smear microscopy and DNA-based diagnostics) and drugs for treatment, challenges like drug resistance, lower diagnostic sensitivity such as microscopy, instrumentation and high-level operational expertise requirement and poor vaccine efficacy pose a greater hinderance to TB monitoring and control. The inability of the BCG vaccine to protect against TB other than disseminated disease in neonates call for innovative approaches to provide improved interventions. This review highlights the potential of multi-omics as a powerful emerging tool offering a holistic insight into the intricate interplay between pathogens and the host immune response. It discusses the potential of multi-omics for discovering biomarkers as targets for rational drug design, production of more effective vaccines and as stable targets for production of universally applicable rapid diagnostics for early and accurate TB detection as well as monitoring treatment.

Structural basis for the inhibition of coronaviral main proteases by PF-00835231.

The main protease (M pro) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M pro. Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M pro and seven M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M pros. In addition, the crystal structures of SARS-CoV-2 M pro, SARS-CoV M pro, MERS-CoV M pro, and seven SARS-CoV-2 M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M pros. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M pro inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.

Characterizing and improving the performance of molten-salt-steam heat exchangers in concentrating solar power plants

Shell-and-tube heat exchangers (HXs) for steam generation from molten salts in concentrating solar power (CSP) plants experience thermal fatigue due to significant temperature gradients and inherent transient operation. Molten salt-steam HX design lifespans exceed actual lifespans, and, as a consequence, designers overpredict plant profitability and operators neglect appropriate prescriptions to optimize these lifetimes. This study refines HX lifespan estimates with data benchmarked against thermal-fluid mechanical modeling of stress and accumulated fatigue. Reduced-order thermal models of the molten salt-steam, shell-and-tube evaporator and superheater predict transient temperature profiles along the two HXs salt-steam flow paths. The modeled evaporator and superheater temperature profiles enable assessment of cyclic stresses within the HX tubesheets, where molten-salt HX failures are most common. Evaporator and superheater performance data from a current 110 MWelec commercial CSP plant provide a basis for validating the reduced-order HX models. HX life predictions derived from stochastic failure distributions serve as inputs for simulating and optimizing existing plant operations. The impact of the updated lifespans on overall plant revenue depends on operating scenarios. This study suggests that typical ramping rates for a CSP plant with a high-temperature Rankine cycle result in an evaporator and superheater life of approximately 10 and 25 years, respectively, compared to the design target of 30 years. Reduced HX lifespans decrease operational plant revenue on average by 4.6-5.1%. Furthermore, there may be as many as four HX replacements over the 30-year lifetime of the plant; and, purchase agreement loss due to failure to meet contractual production requirements can have ramifications that include the risk of bankruptcy.

Siah2- and LRSAM1-mediated K63-linked ubiquitination of snakehead vesiculovirus nucleoprotein facilitates viral replication.

Ubiquitination of viral protein plays an important role in viral replication. However, the ubiquitination of the nucleoprotein (N) of negative-strand RNA viruses has rarely been investigated. This study aimed at investigating the ubiquitination of the N protein of a fish rhabdovirus SHVV (snakehead vesiculovirus), identifying the related host E3 ubiquitin ligases, and determining the role of SHVV N ubiquitination and host E3 ubiquitin ligases in viral replication. We found that SHVV N was ubiquitinated mainly via K63-linked ubiquitination, which was mediated by host E3 ubiquitin ligases Siah2 (Siah E3 ubiquitin protein ligase 2) and LRSAM1 (leucine-rich repeat and sterile alpha motif containing 1). The data suggested that Siah2 and LRSAM1 were hijacked by SHVV to ubiquitinate the N protein for viral replication, which exhibited novel anti-SHVV targets for drug design.

Indirect drive ICF design study for a 3 MJ NIF enhanced yield capability

A proposed upgrade to the National Ignition Facility is under consideration that would ultimately increase the maximum operating envelope for the laser to 3.0 MJ with a peak power of 450 TW. This upgrade would provide opportunities to address an expanded set of data needs for NNSA’s Stockpile Stewardship mission, including the potential to generate fusion yields ≥30 megajoules. A simplified model of ignition and burn is used to scope the theoretical maximum target yield as a function of laser driver energy. We examine two indirect drive ICF target designs that make use of the 3 MJ laser drive using a common model for integrated laser-hohlraum simulations. These two designs compare and contrast the impacts of two different ablator materials, pure carbon and CH. Additionally, the potential for increased backscatter from these larger scale designs is discussed.

Dual-Layer Nanoengineered Urinary Catheters for Enhanced Antimicrobial Efficacy and Reduced Cytotoxicity.

Catheter-associated urinary tract infection (CAUTI) is the most common healthcare-associated infection; however, current therapeutic strategies remain insufficient for standard clinical application. A novel urinary catheter featuring a dual-layer nanoengineering approach using zinc (Zn) and silver nanoparticles (AgNPs) is successfully fabricated. This design targets microbial resistance, minimizes cytotoxicity, and maintains long-term efficacy. The inner AgNPs layer provides immediate antibacterial effects against the UTI pathogens, while the outer porous Zn layer controls zero-order Ag release and generates reactive oxygen species, thus enhancing long-term bactericidal performance. Enhanced antibacterial properties of Zn/AgNPs-coated catheters are observed, resulting in 99.9% of E. coli and 99.7% of S. aureus reduction, respectively. The Zn/AgNPs-coated catheter significantly suppresses biofilm with sludge formation compared to AgNP-coated and uncoated catheters (all, p<0.05). The Zn/AgNP-coated catheter in a rabbit model demonstrated a durable, effective barrier against bacterial colonization, maintaining antimicrobial properties during the catheter indwelling period with significantly reduced inflammation and epithelial disruption compared with AgNP and uncoated groups. This innovation has the potential to revolutionize the design of antimicrobial medical devices, particularly for applications requiring long-term implantation. Although further preclinical studies are required to verify its efficacy and safety, this strategy seems to be a promising approach to preventing CAUTI-related complications.

Leveraging plant functional traits in the design of nature‐based solutions: A research agenda

Abstract Nature‐based solutions (NbS) involve interventions that modify ecosystems to enhance multiple ecosystem services (ES). Yet, despite our increasing knowledge of the key role that functional traits play in determining ES, certain types of NbS often do not consider a functional trait perspective. A reason for this lack of translation may be the range of NbS approaches and levels of knowledge of trait–ES relationships. Functional traits may be most useful as targets for NbS design when knowledge on trait–ES mapping is established and the NbS involves a medium or high level of management intervention. A richer understanding of causality in trait–ES and trait–resilience linkages, and context dependency in those linkages, is needed to broaden the application of functional traits in NbS. An improved understanding of trait linkages with cultural ES and how traits interact with stakeholder values to shape NbS uptake would also improve application. Synthesis: A greater consideration of functional traits will increase the efficacy of NbS projects, and could be accelerated by tackling gaps in knowledge about functional traits. Here, we envision a research agenda that both advances NbS design and leverages the varied objectives of NbS to robustly test our knowledge about functional traits.

Genomic Insights into Bacterial Antimicrobial Resistance Transmission and Mitigation Strategies.

The rapid emergence and global spread of antimicrobial resistance in recent years have raised significant concerns about the future of modern medicine. Superbugs and multidrugresistant bacteria have become endemic in many parts of the world, raising the specter of untreatable infections. The overuse and misuse of antimicrobials over the past 80 years have undoubtedly contributed to the development of antimicrobial resistance, placing immense pressure on healthcare systems worldwide. Nonetheless, the molecular mechanisms underlying antimicrobial resistance in bacteria have existed since ancient times. Some of these mechanisms and processes have served as the precursors of current resistance determinants, highlighting the ongoing arms race between bacteria and their antimicrobial adversaries. Moreover, the environment harbors many putative resistance genes, yet we cannot still predict which of these genes will emerge and manifest as pathogenic resistance phenotypes. The presence of antibiotics in natural habitats, even at sub-inhibitory concentrations, may provide selective pressures that favor the emergence of novel antimicrobial resistance apparatus and, thus, underscores the need for a comprehensive understanding of the factors driving the persistence and spread of antimicrobial resistance. As the development of antimicrobial strategies that evade resistance is urgently needed, a clear perception of these critical factors could ultimately pave the way for the design of innovative therapeutic targets.

A direct and analytical method for inverse problems under uncertainty in energy system design: combining inverse simulation and Polynomial Chaos theory

This article introduces and formalizes a novel stochastic method that combines inverse simulation with the theory of generalized Polynomial Chaos (gPC) to solve and study inverse problems under uncertainty in energy system design applications. The method is particularly relevant to design tasks where only a deterministic forward model of a physical system is available, in which a target design quantity is an input to the model that cannot be obtained directly, but can be quantified reversely via the outputs of the model. In this scenario, the proposed method offers an analytical and direct approach to invert such system models. The method puts emphasis on user-friendliness, as it enables its users to conduct the inverse simulation under uncertainty directly in the gPC domain by redefining basic algebra operations for computations. Moreover, the method incorporates an optimization-based approach to integrate supplementary constraints on stochastic quantities. This feature enables the solution of inverse problems bounding the statistical moments of stochastic system variables. The authors exemplify the application of the proposed method with proof-of-concept tests in energy system design, specifically performing uncertainty quantification and sensitivity analysis for a Multi-Energy System (MES). The findings demonstrate the high accuracy of the method as well as clear advantages over conventional sampling-based methods when dealing with a small number of stochastic variables in a system or model. However, the case studies also highlight the current limitations of the proposed method such as slow execution speed due to the optimization-based approach and the challenges associated with, for example, the curse of dimensionality in gPC.

Structure-guided drug design targeting Abl kinase: how structure and regulation can assist in designing new drugs.

The human protein Abelson kinase (Abl), a tyrosine kinase, plays a pivotal role in developing chronic myeloid leukemia (CML). Abl's involvement in various signaling pathways underscores its significance in regulating fundamental biological processes, including DNA damage responses, actin polymerization, and chromatin structural changes. The discovery of the Bcr-Abl oncoprotein, resulting from a chromosomal translocation in CML patients, revolutionized the understanding and treatment of the disease. The introduction of targeted therapies, starting with interferon-alpha and culminating in the development of tyrosine kinase inhibitors (TKIs) like imatinib, significantly improved patient outcomes. However, challenges such as drug resistance and side effects persist, indicating the necessity of research into novel therapeutic strategies. This review describes advancements in Abl kinase inhibitor development, emphasizing rational compound design from structural and regulatory information. Strategies, including bivalent inhibitors, PROTACs, and compounds targeting regulatory domains, promise to overcome resistance and minimize side effects. Additionally, leveraging the intricate structure and interactions of Bcr-Abl may provide insights into developing inhibitors for other kinases. Overall, this review highlights the importance of continued research into Abl kinase inhibition and its broader implications for therapeutic interventions targeting kinase-driven diseases. It provides valuable insights and strategies that may guide the development of next-generation therapies.

Design of a 3D-printed liquid lithium divertor target plate and its interaction with high-density plasma

A liquid Li divertor is a promising alternative for future fusion devices. In this work a new divertor model is proposed, which is processed by 3D-printing technology to accurately control the size of the internal capillary structure. At a steady-state heat load of 10 MW m−2, the thermal stress of the tungsten target is within the bearing range of tungsten by finite-element simulation. In order to evaluate the wicking ability of the capillary structure, the wicking process at 600 °C was simulated by FLUENT. The result was identical to that of the corresponding experiments. Within 1 s, liquid lithium was wicked to the target surface by the capillary structure of the target and quickly spread on the target surface. During the wicking process, the average wicking mass rate of lithium should reach 0.062 g s−1, which could even supplement the evaporation requirement of liquid lithium under an environment > 950 °C. Irradiation experiments under different plasma discharge currents were carried out in a linear plasma device (SCU-PSI), and the evolution of the vapor cloud during plasma irradiation was analyzed. It was found that the target temperature tends to plateau despite the gradually increased input current, indicating that the vapor shielding effect is gradually enhanced. The irradiation experiment also confirmed that the 3D-printed tungsten structure has better heat consumption performance than a tungsten mesh structure or multichannel structure. These results reveal the application potential and feasibility of a 3D-printed porous capillary structure in plasma-facing components and provide a reference for further liquid−solid combined target designs.

Structural Mapping of Polyclonal IgG Responses to HA After Influenza Virus Vaccination or Infection.

Cellular and molecular characterization of immune responses elicited by influenza virus infection and seasonal vaccination have informed efforts to improve vaccine efficacy, breadth, and longevity. Here, we use negative stain electron microscopy polyclonal epitope mapping (nsEMPEM) to structurally characterize the humoral IgG antibody responses to hemagglutinin (HA) from human patients vaccinated with a seasonal quadrivalent flu vaccine or infected with influenza A viruses. Our data show that both vaccinated and infected patients had humoral IgGs targeting highly conserved regions on both H1 and H3 subtype HAs, including the stem and anchor, which are targets for universal influenza vaccine design. Responses against H1 predominantly targeted the central stem epitope in infected patients and vaccinated donors, whereas head epitopes were more prominently targeted on H3. Responses against H3 were less abundant, but a greater diversity of H3 epitopes were targeted relative to H1. While our analysis is limited by sample size, on average, vaccinated donors responded to a greater diversity of epitopes on both H1 and H3 than infected patients. These data establish a baseline for assessing polyclonal antibody responses in vaccination and infection, providing context for future vaccine trials and emphasizing the importance of carefully designing vaccines to boost protective responses towards conserved epitopes.

Investigating worldwide strong motion databases to derive a collection of free-field records to select design-compatible waveforms for Switzerland

The process of choosing ground motions typically relies on assembling a collection of ground motions that match a desired spectrum. This selection process is guided by specific seismological criteria, including factors like earthquake magnitude, distance from the epicenter, site soil type, and the range of spectral periods that need to fit with the target spectrum. The selection algorithm and the available dataset of waveforms obviously play significant roles in this process. In many engineering and site response applications, it is essential that the input ground motion is representative for the shaking at the free surface of the Earth, and at times also a specific soil type may be required. However, real waveform databases often lack sufficient and/or consistent metadata related to the installation type and soil characterization of recording stations, as well as to the earthquake seismological parameters. This deficiency can lead to the selection of inappropriate waveforms, such as those recorded by stations situated within manmade structures (buildings, bridges, dams) or on a soil type different than the intended one. To address this issue, our approach for creating an appropriate waveform database applicable to Switzerland starts with the computation of seismic hazard disaggregation for return periods of 475 and 975 years. This computation helps identifying the magnitude-distance scenarios most relevant for the five seismic hazard zones defined in the Swiss building code. Once these magnitude-distance ranges are identified, we adhere to established standards regarding the quality control of three-component waveforms and their associated metadata. We assemble a database of waveforms by collating and homogenizing data from available global databases. In the interest of comprehensiveness, we also incorporate data obtained from 3D physics-based numerical simulations of strong-motion near the seismic source. Finally, we employ an algorithm that integrates the Eurocode 8 waveform selection criteria. This algorithm allows us to select and scale waveforms suitable for microzonation and structural analysis studies within each of Switzerland’s five seismic hazard zones. Selecting waveforms compatible with the target design spectra proves to be challenging due to the stringent criteria imposed by Eurocode 8. This challenge arises from the scarcity of recorded waveforms with verified metadata and precise site characterization in the desired magnitude-distance ranges.

Effector MoSDT1 enhances Magnaporthe oryzae virulence and plays a dual role in regulating rice defense.

C2H2 zinc effectors are a class of pathogen proteins that play a dual role in plant-pathogen interactions, promoting pathogenicity and enhancing plant defense. In our previous research, we identified Magnaporthe oryzae Systemic Defense Trigger 1 (MoSDT1) as a C2H2 zinc effector that activates rice (Oryza sativa) defense when overexpressed in rice. However, its regulatory roles in pathogenicity and defense require further investigation. In this study, we generated an MoSDT1 overexpressing strain and 2 knockout strains of M. oryzae to assess the impact of MoSDT1 on pathogenicity, rice defense, and phenotypic characteristics. Our analyses revealed that MoSDT1 substantially influenced vegetative growth, conidia size, and conidiation, and was crucial for the virulence of M. oryzae while suppressing rice defense. MoSDT1 localized to the nucleus and cytoplasm of rice, either dependent or independent of M. oryzae delivery. Through RNA-seq, scRNA-seq, and ChIP-seq, we identified that MoSDT1 modulates rice defense by regulating the phosphorylation and ubiquitination of various rice signaling proteins, including transcription factors, transcription repressors, kinases, phosphatases, and the ubiquitin system. These findings provide valuable insights into the regulatory mechanisms of C2H2 zinc finger effector proteins and offer important foundational information for utilizing their target genes in disease resistance breeding and the design of targets for disease management.