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“Undruggable” targets such as KRAS are particularly challenging in the development of drugs. We devised a novel chemical knockdown strategy, CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics) technology, which promotes protein degradation using small molecules (CANDDY molecules) that are conjugated to a degradation tag (CANDDY tag) modified from proteasome inhibitors. We demonstrated that CANDDY tags allowed for direct proteasomal target degradation independent of ubiquitination. We synthesized a KRAS-degrading CANDDY molecule, TUS-007, which induced degradation in KRAS mutants (G12D and G12V) and wild-type KRAS. We confirmed the tumor suppression effect of TUS-007 in subcutaneous xenograft models of human colon cells (KRAS G12V) with intraperitoneal administrations and in orthotopic xenograft models of human pancreatic cells (KRAS G12D) with oral administrations. Thus, CANDDY technology has the potential to therapeutically target previously undruggable proteins, providing a simpler and more practical drug targeting approach and avoiding the difficulties in matchmaking between the E3 enzyme and the target.

Marine organisms are a rich source of bioactive secondary metabolites. Although many marine natural products with bioactivities have been isolated, successful elucidation of their mechanisms of action remains limited. In this study, we prepared a probe molecule based on the marine cyclic peptide kapakahine A (1) by introducing a linker with an azide terminal group, which enables the introduction of fluorescent groups for the effective monitoring of subcellular localization, or coupling to affinity beads for the pull-down of target proteins. The results of LC/MS/MS measurements, ProteinPilot analysis, and Western blotting suggest that kapakahine A interacts with the mitochondrial inner membrane proteins PHB1, PHB2, and ANT2, which is consistent with the results of the subcellular localization analysis using a fluorescent probe.

Target protein degradation has emerged as a promising strategy for the discovery of novel therapeutics during the last decade. Proteolysis-targeting chimera (PROTAC) harnesses a cellular ubiquitin-dependent proteolysis system for the efficient degradation of a protein of interest. PROTAC consists of a target protein ligand and an E3 ligase ligand so that it enables the target protein degradation owing to the induced proximity with ubiquitin ligases. Although a great number of PROTACs has been developed so far using previously reported ligands of proteins for their degradation, E3 ligase ligands have been mostly limited to either CRBN or VHL ligands. Those PROTACs showed their limitation due to the cell type specific expression of E3 ligases and recently reported resistance toward PROTACs with CRBN ligands or VHL ligands. To overcome these hurdles, the discovery of various E3 ligase ligands has been spotlighted to improve the current PROTAC technology. This review focuses on currently reported E3 ligase ligands and their application in the development of PROTACs.

Background Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integrated large-scale plasma cis-pQTLs data and telomere length GWAS datasets. We used Mendelian randomization(MR) to identify drug target proteins for telomere length, providing essential clues for future precision therapy and targeted drug development. Methods Using plasma cis-pQTLs data from a previous GWAS study (3,606 Pqtls associated with 2,656 proteins) and a GWAS dataset of telomere length (sample size: 472,174; GWAS ID: ieu-b-4879) from UK Biobank, using MR, external validation, and reverse causality testing, we identified essential drug target proteins for telomere length. We also performed co-localization, Phenome-wide association studies and enrichment analysis, protein-protein interaction network construction, search for existing intervening drugs, and potential drug/compound prediction for these critical targets to strengthen and expand our findings. Results After Bonferron correction ( p  < 0.05/734), RPN1 (OR: 0.96; 95%CI: (0.95, 0.97)), GDI2 (OR: 0.94; 95%CI: (0.92, 0.96)), NT5C (OR: 0.97; 95%CI: (0.95, 0.98)) had a significant negative causal association with telomere length; TYRO3 (OR: 1.11; 95%CI: (1.09, 1.15)) had a significant positive causal association with telomere length. GDI2 shared the same genetic variants with telomere length (coloc.abf-PPH 4 > 0.8). Conclusion Genetically determined plasma RPN1, GDI2, NT5C, and TYRO3 have significant causal effects on telomere length and can potentially be drug targets. Further exploration of the role and mechanism of these proteins/genes in regulating telomere length is needed.

The regio- and stereoselectivity and the molecular mechanisms of the [3 + 2] cycloaddition reactions between Syn-propanethial S-oxide and selected conjugated nitroalkenes were explored theoretically in the framework of the Molecular Electron Density Theory. It was found that cycloadditions with the participation of nitroethene as well as its methyl- and chloro-substituted analogs can be realized via a single-step mechanism. On the other hand, [3 + 2] cycloaddition reactions between Syn-propanethial S-oxide and 1,1-dinitroethene can proceed according to a stepwise mechanism with a zwitterionic intermediate. Finally, we evaluated the affinity of model reaction products for several target proteins: cytochrome P450 14α-sterol demethylase CYP51 (RSCB Database PDB ID: 1EA1), metalloproteinase gelatinase B (MMP-9; PDB ID: 4XCT), and the inhibitors of cyclooxygenase COX-1 (PDB:3KK6) and COX-2 (PDB:5KIR).

It has been reported that ginsenoside Rg1 (G-Rg1) can alleviate alcoholic liver injury, cardiac hypertrophy and myocardial ischemia, as well as reperfusion injury. Therefore, the present study aimed to investigate the role of G-Rg1 in alcohol-induced myocardial injury, as well as to elucidate its underlying mechanisms of action. For this purpose, H9c2 cells were stimulated with ethanol. Subsequently, H9c2 cell viability and apoptosis were determined using a Cell Counting Kit-8 assay and flow cytometric analysis, respectively. The levels of lactate dehydrogenase and caspase-3 in the H9c2 cell culture supernatant were detected using corresponding assay kits. In addition, the expression of green fluorescent protein (GFP)-light chain 3 (LC3) and that of C/EBP homologous protein (CHOP) were evaluated using GFP-LC3 assay and immunofluorescence staining, respectively. The expression levels of apoptosis-, autophagy-, endoplasmic reticulum stress (ERS)- and adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway-related proteins were detected using western blot analysis. The results revealed that treatment with G-Rg1 enhanced the viability and suppressed the apoptosis of ethanol-stimulated H9c2 cells. G-Rg1 also attenuated autophagy and ERS in ethanol-stimulated H9c2 cells. In addition, the levels of phosphorylated (p)-protein kinase R (PKR)-like ER kinase (PERK), p-eukaryotic translation initiation factor 2a, activating transcription factor 4 (ATF4), CHOP, caspase-12 and p-AMPK were downregulated, while the p-mTOR level was upregulated in ethanol-stimulated H9c2 cells treated with G-Rg1. Furthermore, the co-treatment of G-Rg1-treated ethanol-stimulated H9c2 cells with AICAR, an AMPK agonist, or CCT020312, a PERK agonist, inhibited cell viability and promoted cell apoptosis, autophagy and ERS. Overall, the results of the present study suggest that G-Rg1 suppresses autophagy and ERS via inhibiting the AMPK/mTOR and PERK/ATF4/CHOP pathways to alleviate ethanol-induced H9c2 cell injury.

Marine drugs have long been used and exhibit unique advantages in clinical practices. Among the marine drugs that have been approved by the Food and Drug Administration (FDA), the protein–ligand interactions, such as cytarabine–DNA polymerase, vidarabine–adenylyl cyclase, and eribulin–tubulin complexes, are the important mechanisms of action for their efficacy. However, the complex and multi-targeted components in marine medicinal resources, their bio-active chemical basis, and mechanisms of action have posed huge challenges in the discovery and development of marine drugs so far, which need to be systematically investigated in-depth. Molecular docking could effectively predict the binding mode and binding energy of the protein–ligand complexes and has become a major method of computer-aided drug design (CADD), hence this powerful tool has been widely used in many aspects of the research on marine drugs. This review introduces the basic principles and software of the molecular docking and further summarizes the applications of this method in marine drug discovery and design, including the early virtual screening in the drug discovery stage, drug target discovery, potential mechanisms of action, and the prediction of drug metabolism. In addition, this review would also discuss and prospect the problems of molecular docking, in order to provide more theoretical basis for clinical practices and new marine drug research and development.

Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand of the protein of interest (POI) and the specific ligand of E3 ubiquitin ligase, respectively, via a suitable linker. PROTAC degradation of the target protein is performed through the ubiquitin–proteasome system (UPS). The general process is that PROTAC binds to the target protein and E3 ligase to form a ternary complex and label the target protein with ubiquitination. The ubiquitinated protein is recognized and degraded by the proteasome in the cell. At present, PROTAC, as a new type of drug, has been developed to degrade a variety of cancer target proteins and other disease target proteins, and has shown good curative effects on a variety of diseases. For example, PROTACs targeting AR, BR, BTK, Tau, IRAK4, and other proteins have shown unprecedented clinical efficacy in cancers, neurodegenerative diseases, inflammations, and other fields. Recently, PROTAC has entered a phase of rapid development, opening a new field for biomedical research and development. This paper reviews the various fields of targeted protein degradation by PROTAC in recent years and summarizes and prospects the hot targets and indications of PROTAC.

The 5th International Symposium on Frontiers in Molecular Science was held on 26–29 August 2025 in Kyoto (Japan), with the support of Kyoto Prefectural University and Kyoto Prefectural University of Medicine. It is evident that the event has proven to be significant, showcasing presentations of pioneering research achievements by internationally renowned researchers and fostering numerous stimulating discussions. The symposium’s objective was to identify and select key research themes within the domain of molecular science. Three plenary lecturers and numerous researchers of outstanding merit were invited by chairs to deliver keynote and invited lectures across six fields: S1. Protein Structure and Molecular Dynamics; S2. Enzymes; S3. Membrane Proteins; S4. Cancer Target Proteins; S5. Drug Design and Solution to Drug Resistance Problem; S6. Physiological Functions of Proteins and Organ Interactions. A total of 185 scientists from 31 countries/regions participated in the symposium with 139 presentations. We would like to express our sincere gratitude to the 31 members of the Scientific Committee and the seven members of the Local Organizing Committee who contributed to enhancing the quality of this symposium, ensuring its smooth operation, and dedicating considerable effort to the selection of each award.

Five to 10% of the coronavirus SARS-CoV-2-infected patients, i.e., with new coronavirus disease 2019 (COVID-19), are presenting with an acute respiratory distress syndrome (ARDS) requiring urgent respiratory and hemodynamic support in the intensive care unit (ICU). However, nutrition is an important element of care. The nutritional assessment and the early nutritional care management of COVID-19 patients must be integrated into the overall therapeutic strategy. The international recommendations on nutrition in the ICU should be followed. Some specific issues about the nutrition of the COVID-19 patients in the ICU should be emphasized. We propose a flow chart and ten key issues for optimizing the nutrition management of COVID-19 patients in the ICU.