Article
Gastroenterology & Hepatology
Zahra Hasanshahi, Ava Hashempour, Farzane Ghasabi, Javad Moayedi, Zahra Musavi, Behzad Dehghani, Heidar Sharafi, Hassan Joulaei
Summary: In Iranian patients with initial HCV infection, various amino acid residue changes were found in NS5A and NS5B proteins, but no mutations related to treatment resistance were discovered in NS5B. Bioinformatics analysis revealed strong interactions between inhibitors, NS5A and NS5B proteins, and a lack of efficient drug resistance mutations in the analyzed sequences.
BMC GASTROENTEROLOGY
(2021)
Article
Engineering, Biomedical
Yao Lu, Qingqing Pan, Wenxia Gao, Yuji Pu, Kui Luo, Bin He, Zhongwei Gu
Summary: Disulfiram (DSF) has been used as an alcoholism drug for 70 years and has recently gained attention for its anticancer activity. However, the oral delivery of DSF in clinical settings has not yielded satisfactory outcomes, calling for a deeper understanding of its mechanisms and limitations. This review provides a critical summary of the molecular biological anticancer mechanisms of DSF/Cu2+ and explains the challenges of oral DSF delivery in clinical oncology. It also highlights recent advances in DSF/Cu2+ delivery strategies and emerging treatment regimens for cancer therapy.
Review
Pharmacology & Pharmacy
Ying-Shan Ren, Hui-Lin Li, Xiu-Hong Piao, Zhi-You Yang, Shu-Mei Wang, Yue-Wei Ge
Summary: DARTS is a novel target discovery approach that is particularly adept at screening small molecule targets without requiring any structural modifications. It can reveal drug-target interactions from cells or tissues and has been applied to uncover drug-action mechanisms.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Cell Biology
Woan-Ing Twu, Ji-Young Lee, Heeyoung Kim, Vibhu Prasad, Berati Cerikan, Uta Haselmann, Keisuke Tabata, Ralf Bartenschlager
Summary: Although the viral DMVs are structurally similar to autophagosomes, traditional macroautophagy is not essential for the replication of HCV and SARS-CoV-2. These viruses instead utilize factors involved in autophagosome formation, particularly class III phosphatidylinositol 3-kinase (PI3K).
Article
Chemistry, Multidisciplinary
Hao Zhang, Tingting Wang, Hanghang Liu, Yaobao Han, Qing Zheng, Qi Xu, Bolin Bao, Wei Xing, Zhen Li
Summary: This study reports an innovative therapy for hepatocellular carcinoma (HCC) by forming and amplifying a vicious cycle between mitochondrial oxidative stress and endoplasmic reticulum (ER) stress. The combination of biodegradable ultrasmall Cu2-xSe nanoparticles (CS NPs) and the alcohol-abuse drug disulfiram (DSF) significantly suppresses the growth of HCC and exhibits excellent anti-tumor effects. The formed CuET complex immobilizes NPL4, induces ER stress and mitochondrial oxidative stress, leading to severe apoptosis of tumor cells and a notable decrease in tumor size.
Article
Infectious Diseases
Sebastian Schroepf, Daniela Burau, Hans-Georg Muench, Hartmut Derendorf, Markus Zeitlinger, Orsolya Genzel-Boroviczeny, Dieter Adam, Charlotte Kloft
Summary: This study, dedicated to the memory of pharmacokinetics pioneer Hartmut Derendorf, explores the feasibility and safety of microdialysis sampling for vancomycin monitoring in septic infants/neonates. The results demonstrated the applicability of microdialysis for vancomycin monitoring, with well-tolerated sampling and plausible pharmacokinetic profiles obtained. Further larger trials are warranted to characterize the pharmacokinetics and variability of vancomycin at the target site in vulnerable patients.
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
(2021)
Article
Microbiology
Diogo Ramos, Miguel Pinto, Rodrigo Sousa Coutinho, Carolina Silva, Miriam Quina, Joao Paulo Gomes, Elizabeth Padua
Summary: Hepatitis C virus (HCV) is prevalent among vulnerable populations such as injection drug users (IDU) in Portugal. HCV has high intra-host variability, and selecting driving forces may lead to the emergence of resistance-associated substitutions (RAS) that reduce treatment effectiveness. This study aimed to analyze the sequence variation of NS5A in treatment-naive IDU using Sanger and Next-Generation sequencing (NGS), and confirm HCV subtypes.
Article
Biochemistry & Molecular Biology
Ming-Chao Tsai, Chao-Hung Hung, Sheng-Nan Lu, Jing-Houng Wang, Chien-Hung Chen, Kwong-Ming Kee, Kuo-Chin Chang, Tsai-Ling Chao, Tsung-Hui Hu
Summary: In chronic HCV-infected individuals in Taiwan, RAVs in the NS5A region were prevalent, especially M28V and Y93H in genotype 1a and 1b, respectively, with associations to high HCV RNA levels and low rGT levels. Multivariate analysis identified HCV RNA levels and rGT as risk factors associated with the presence of RAVs. There was no association between the presence of RAVs and no SVR.
BIOMEDICAL JOURNAL
(2021)
Article
Chemistry, Multidisciplinary
Max E. Huber, Lara Toy, Maximilian F. Schmidt, Dorothee Weikert, Matthias Schiedel
Summary: This article discusses recent approaches that utilize cellular target engagement studies in the development of intracellular allosteric GPCR antagonists. These methods play a critical role in evaluating IABS-targeted ligands as potential therapeutic agents.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Review
Genetics & Heredity
Lei Xu, Xiaoqing Ru, Rong Song
Summary: Machine learning methods have become mainstream in predicting drug-target interactions, utilizing large amounts of existing data and innovative technologies to potentially save time and costs. The characteristics and issues of various machine learning algorithms need further exploration for constructing efficient models.
FRONTIERS IN GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Yang Zheng, Susanne Schroeder, Georgi K. Kanev, Sanaa S. Botros, Samia William, Abdel-Nasser A. Sabra, Louis Maes, Guy Caljon, Carmen Gil, Ana Martinez, Irene G. Salado, Koen Augustyns, Ewald Edink, Maarten Sijm, Erik de Heuvel, Iwan J. P. de Esch, Tiffany van der Meer, Marco Siderius, Geert Jan Sterk, David Brown, Rob Leurs
Summary: This study investigated the potential of Schistosoma mansoni phosphodiesterase SmPDE4A as a new drug target for schistosomiasis. The researchers cloned, isolated, and characterized the full-length and catalytic domains of SmPDE4A. They found that SmPDE4A resembles human PDE4 more than parasite PDEs. Screening of PDE inhibitors identified tetrahydrophthalazinones and benzamides as potential hits, but further evaluation showed that the inhibitors were not effective against S. mansoni, suggesting that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Sooin Kim, Sanggil Kim, Sangji Kim, Namkyoung Kim, Sang Won Lee, Hanbin Yi, Seungeun Lee, Taebo Sim, Yongseok Kwon, Hyun Soo Lee
Summary: A novel method for traceless affinity-directed intact protein labeling is established using small binding proteins and genetic code expansion technology. This approach enables site-specific antibody labeling and the production of highly effective antibody-drug conjugates specifically targeting breast cancer cell lines.
Review
Pharmacology & Pharmacy
Laurence Lafanechere
Summary: Microtubule-targeting compounds are effective in cancer therapy but come with adverse effects on non-cancerous cells. Advancements in understanding microtubule structure and dynamics have led to new therapeutic strategies for cancer and other diseases. Collaboration between chemists and biologists is key in selecting improved microtubule-targeting drugs.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Immunology
Juliana Almeida-Silva, Diego Silva Menezes, Juan Mateus Pereira Fernandes, Marcio Cerqueira Almeida, Deyvison Rhuan Vasco-dos-Santos, Roberto Magalhaes Saraiva, Alessandra Lifsitch Vicosa, Sandra Aurora Chavez Perez, Sonia Gumes Andrade, Ana Marcia Suarez-Fontes, Marcos Andre Vannier-Santos
Summary: This study tested the combination therapy of benznidazole (BZ) and the repositioned drug disulfiram (DSF) and its derivative diethyldithiocarbamate (DETC) on Trypanosoma cruzi. The results showed that the DETC-BZ combination had a synergistic effect in reducing parasite proliferation and decreasing toxicity. The combination therapy also showed efficacy against drug-resistant strains of Trypanosoma cruzi.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yujun Han, Ying Sun, Hong Ma, Ruolin Wang, Yuning Lan, Haifeng Gao, Zhaofeng Huang
Summary: Wild oat is a common and problematic weed in wheat fields in China, and controlling it has become increasingly difficult. This study aimed to identify the molecular basis of clodinafop-propargyl resistance in wild oat. Two resistant populations were found to have high resistance to fenoxaprop-p-ethyl, low resistance to clethodim and pinoxaden, but they were sensitive to mesosulfuron-methyl and pyroxsulam. An Ile2041-Asn mutation was identified in both resistant plants. The resistant populations also showed metabolic resistance, which was confirmed by the application of inhibitors.
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sashank Agrawal, Monika Jain, Wei-Zen Yang, Hanna S. Yuan
Summary: This study compared the biochemical and biophysical properties of TDP-43 truncated proteins with and without the P112H mutation, revealing that the mutated proteins have higher thermal stability, impaired RNA-binding activity, and reduced aggregation propensity. The P112H mutation causes local conformational changes in TDP-43, disrupting interactions with nucleic acids. These findings suggest that the P112H mutation contributes to frontotemporal dementia through functional impairment of RNA metabolism and changes in protein clearance mechanisms.
Article
Chemistry, Multidisciplinary
Cedric Grauffel, Wei-Hsiang Weng, Todor Dudev, Carmay Lim
Summary: Lithium is a first-line therapy for bipolar disorder, but its therapeutic mechanism is still unclear. Research shows that lithium can compete with Mg2+ and Na+ to regulate signaling proteins, reducing abnormal signaling in bipolar patients. Lithium may also affect the activity of PKC, lowering hyperactivity in bipolar patients.
Article
Chemistry, Medicinal
Yao Chi Chen, Yu-Hsien Chen, Jon D. Wright, Carmay Lim
Summary: Single-point mutations can disrupt protein-protein interactions and lead to diseases and drug resistance. By manually curating mutations that significantly impair or disrupt PPIs, we have expanded the number of distinct PPI hot spots. These hot spots, along with available structures, have been collected in a database called PPI-Hotspot(DB) and can be used for predicting and understanding PPI hot spots.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Wen-Hao Tsai, Cedric Grauffel, Ming-Yueh Huang, Sandra Postic, Marjan Slak Rupnik, Carmay Lim, Shi-Bing Yang
Summary: This study investigates the effect of extracellular pH on the gating mechanism of alkaline-activated K2P channel TALK1. The results show that R233 acts as the primary pH sensor and regulates the conformational changes of the potassium-binding site through an interacting network. The acidic pH-activated R233E mutant can recapitulate the network interactions of protonated R233. The data further suggest stochastic coupling between R233 and the SF gate.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Monika Jain, Bagher Golzarroshan, Chia-Liang Lin, Sashank Agrawal, Wei-Hsuan Tang, Chiu-Ju Wu, Hanna S. Yuan
Summary: This study reveals the molecular mechanism of how Suv3 is assembled into a dimeric helicase for efficient RNA binding and unwinding, and highlights its importance in promoting RNA degradation and maintaining mitochondrial genome integrity and homeostasis.
Article
Chemistry, Multidisciplinary
Karine Mazmanian, Ting Chen, Karen Sargsyan, Carmay Lim
Summary: This study investigates the reactivity of cysteine in proteins using combined quantum mechanical/continuum calculations and identifies novel targets for combating SARS-CoV-2. The researchers propose a multi-targeting strategy that enhances antiviral effects and prevents drug resistance by targeting multiple conserved viral proteins using a Zn-ejector drug.
WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
(2022)
Article
Multidisciplinary Sciences
Karen Sargsyan, Karine Mazmanian, Carmay Lim
Summary: Inferences about viral fitness cannot be made solely from mutagenesis studies of an isolated viral protein. A systematic analysis is lacking in identifying mutations that enhance virus fitness while reducing drug effectiveness. This study presents a general strategy to identify viral mutations that may decrease the efficacy of antiviral drugs targeting M-pro, PLpro, and RdRp in SARS-CoV-2. By analyzing drug-interacting virus residues and selection pressure of virus residues, potential drug target regions and antiviral resistance can be identified. This strategy utilizing genomic sequence and protein structure databases can quickly assess the fitness of emerging virus variants and guide future antiviral drug design.
SCIENTIFIC REPORTS
(2023)
Article
Cell Biology
Sahana Shankar, Zi-Ting Hsu, Artur Ezquerra, Chien-Chien Li, Tzu-Lun Huang, Etienne Coyaud, Ricardo Viais, Cedric Grauffel, Brian Raught, Carmay Lim, Jens Luders, Su-Yi Tsai, Kuo-Chiang Hsia
Summary: This study reveals a y-tubulin ring complex (y-TuRC)-dependent pathway that promotes cilia disassembly and prevents cilia formation. It is further demonstrated that Kif2A is recruited to the cilium basal body in a y-TuRC-dependent manner. These findings illustrate the important role of y-TuRC in ciliogenesis.
Article
Biochemistry & Molecular Biology
Chao-Cheng Cho, Chun-Jung Lin, Hsun-Ho Huang, Wei-Zen Yang, Cheng-Yin Fei, Hsin-Ying Lin, Ming-Shyue Lee, Hanna S. S. Yuan
Summary: Mammalian DNMTs are key DNA methylation enzymes that regulate gene expression and their dysregulation is linked to diseases and carcinogenesis. Non-nucleoside DNMT inhibitors have been identified, but their mechanisms of action are largely unknown.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Physical
Karine Mazmanian, Ceïdric Grauffel, Todor Dudev, Carmay Lim
Summary: This study investigates the competition between Ca2+ and Sr2+ ions at protein Ca2+-binding sites. The research reveals that Ca2+-sites with strongly charged protein ligands that are relatively buried and rigid are resistant to Sr2+ displacement. However, Ca2+-sites crowded with multiple protein ligands that are solvent-exposed and flexible enough to accommodate an additional backbone ligand from the outer shell may be susceptible to Sr2+ displacement. Additionally, solvent-exposed Ca2+ sites with a few weak charge-donating ligands that can rearrange to fit the coordination requirements of strontium are also prone to Sr2+ displacement.
JOURNAL OF PHYSICAL CHEMISTRY B
(2023)
Article
Chemistry, Medicinal
Li-An Chen, Yueh-Hsiang Yu, Wei-Ting Tian, Wei-Chen Lin, Cedric Grauffel, Chun-Yi Wu, Chuan-Lin Chen, Carmay Lim, Hsing-Mao Chu, Tse-Wen Chang, Chi-Jiun Peng
Summary: Antibodies conjugated with diagnostic/therapeutic radionuclides, such as TE-1132, show promise for treating inoperable cancers like pancreatic cancer. TE-1132, composed of α-CA19-9 scFv-Fc conjugated to 3 DOTA chelators, demonstrated high radioactivity and selective tumor accumulation in mouse models. The administration of [Lu-177]Lu-TE-1132 effectively inhibited tumor growth and improved survival without adverse effects.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Cedric Grauffel, Wei-Hsiang Weng, Carmay Lim
Summary: This study found that the net charge of residues in proteins plays a crucial role in determining the selectivity for divalent Ca2+ over monovalent Li+. Neutral/anionic Ca2+-carboxylate sites are resistant to Li+ attack, while cationic Ca2+-sites surrounded by Arg(+)/Lys(+) are prone to Li+ attack.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Biochemistry & Molecular Biology
Ting Chen, Cedric Grauffel, Wei-Zen Yang, Yi-Ping Chen, Hanna S. Yuan, Carmay Lim
Summary: A strategy to inhibit viral protease can help counter viruses causing persistent outbreaks. This study used a method to identify specific regions in viral proteases and found peptides that can bind to these regions. By applying this strategy, pseudosubstrate peptide inhibitors were discovered for the 2A protease of enterovirus 71, which is a key pathogen for hand-foot-and-mouth disease in children.
ACS BIO & MED CHEM AU
(2022)
Article
Chemistry, Medicinal
Ting Chen, Cheng-Yin Fei, Yi-Ping Chen, Karen Sargsyan, Chun-Ping Chang, Hanna S. Yuan, Carmay Lim
Summary: This study targets multiple conserved domains of the SARS-CoV-2 replication and transcription complex (RTC) using clinically safe Zn-ejector drugs disulfiram and ebselen to inhibit key activities of nsp13 and nsp14, showing a synergistic inhibition of viral replication when combined with remdesivir.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2021)
Correction
Chemistry, Multidisciplinary
Karen Sargsyan, Chien-Chu Lin, Ting Chen, Cedric Grauffel, Yi-Ping Chen, Wei-Zen Yang, Jian-Jong Liang, Chun-Che Liao, Yi-Ling Lin, Hanna S. Yuan, Carmay Lim