ACS Pharmacology and Translational Science

Bacterial DNA gyrase, a type IIA DNA topoisomerase that plays an essential role in bacterial DNA replication and transcription, is a clinically validated target for discovering and developing new antibiotics. In this article, based on a supercoiling-dependent fluorescence quenching (SDFQ) method, we developed a high-throughput screening (HTS) assay to identify inhibitors targeting bacterial DNA gyrase and screened the National Institutes of Health's Molecular Libraries Small Molecule Repository library containing 370,620 compounds in which 2891 potential gyrase inhibitors have been identified. According to these screening results, we acquired 235 compounds to analyze their inhibition activities against bacterial DNA gyrase using gel- and SDFQ-based DNA gyrase inhibition assays and discovered 155 new bacterial DNA gyrase inhibitors with a wide structural diversity. Several of them have potent antibacterial activities. These newly discovered gyrase inhibitors include several DNA gyrase poisons that stabilize the gyrase-DNA cleavage complexes and provide new chemical scaffolds for the design and synthesis of bacterial DNA gyrase inhibitors that may be used to combat multidrug-resistant bacterial pathogens. Additionally, this HTS assay can be applied to screen inhibitors against other DNA topoisomerases.

Eddy E. Alfonso

Zifang Deng

Daniel Boaretto

Becky L. Hood

Stefan Vasile

Layton H. Smith

Jeremy W. Chambers

Prem Chapagain

Fenfei Leng

ACS Pharmacology & Translational Science

Novel and Structurally Diversified Bacterial DNA Gyrase Inhibitors Discovered through a Fluorescence-Based High-Throughput Screening Assay

通过基于荧光的高通量筛选实验发现的新型及结构多样化的细菌DNA促旋酶抑制剂

Furin plays a major role in post-translational modification of several biomolecules, including endogenous hormones, growth factors, and cytokines. Recent reports have demonstrated the association of furin and cardio-cerebrovascular diseases (CVDs) in humans. This review describes the possible pathogenic contribution of furin and its substrates in CVDs. Early-stage hypertension and diabetes mellitus show a negative correlation with furin. A reduction in furin might promote hypertension by decreasing maturation of B-type natriuretic peptide (BNP) or by decreasing shedding of membrane (pro)renin receptor (PRR), which facilitates activation of the renin–angiotensin–aldosterone system (RAAS). In diabetes, furin downregulation potentially leads to insulin resistance by reducing maturation of the insulin receptor. In contrast, the progression of other CVDs is associated with an increase in furin, including dyslipidemia, atherosclerosis, ischemic stroke, myocardial infarction (MI), and heart failure. Upregulation of furin might promote maturation of membrane type 1-matrix metalloproteinase (MT1-MMP), which cleaves low-density lipoprotein receptor (LDLR), contributing to dyslipidemia. In atherosclerosis, elevated levels of furin possibly enhance maturation of several substrates related to inflammation, cell proliferation, and extracellular matrix (ECM) deposition and degradation. Neuronal cell death following ischemic stroke has also been shown to involve furin substrates (e.g., MT1-MMP, hepcidin, and hemojuvelin). Moreover, furin and its substrates, including tumor necrosis factor-α (TNF-α), endothelin-1 (ET-1), and transforming growth factor-β1 (TGF-β1), are capable of mediating inflammation, hypertrophy, and fibrosis in MI and heart failure. Taken together, this evidence provides functional significance of furin in CVDs and might suggest a potential novel therapeutic modality for the management of CVDs.

Surasak Wichaiyo

Pimpisid Koonyosying

Noppawan Phumala Morales

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

Furin在心血管疾病中的功能作用

The standard androgen deprivation therapy for advanced prostate cancer includes the use of bicalutamide, which is a well-known antagonist of androgen receptors. Despite numerous benefits of the drugs in prostate cancer treatment, there is always a risk of developing a resistant phenotype, which paves the way for a more aggressive and low-survival type of prostate cancer. Over the years, many studies have investigated the candidate mechanisms of such resistance and have managed to find possible therapeutic solutions. In this Review, we shed light on the heterogeneous dynamics of progression to resistance against bicalutamide treatment, referring to the most recent studies and the approaches that have been so far discussed. This Review tries to offer a deep and comprehensive understanding about how the resistant cells become sensitive to the drug and what corresponding pathways lead to an appropriate solution for the antiandrogen resistance challenge.

Mehrnaz Izady

Fatemeh Khatami

Zeinab Ahadi

Hassan Roudgari

Seyed Mohammad Kazem Aghamir

Updates on Overcoming Bicalutamide Resistance: A Glimpse into Resistance to a Novel Antiandrogen

克服比卡鲁胺耐药性的最新进展：对新型抗雄激素耐药性的窥探

Conventional drug delivery methods to treat testicular disorders face various challenges, which could be circumvented by using targeted drug delivery. Testicular cell targeting ligands, such as Leydig cell homing peptides, would be an excellent choice to achieve the targeted delivery of drugs to the testis. In this study, Leydig cell homing peptides (LCHPs), LCHP1 and LCHP2, were identified via in vitro, followed by in vivo biopanning of a phage display peptide library and next-generation sequencing. Both of the LCHPs were validated in vitro for their specific Leydig cell and in vivo testis targeting potential. Furthermore, molecular targets of the LCHP1 and LCHP2 were identified using affinity purification mass spectrometry (APMS). The LCHP1 and LCHP2 are able to specifically target Leydig cells of the testis and undergo cell internalization as well as target the testis at the in vivo level, hence providing an opportunity to be utilized as a potential ligand for drug delivery to the testis.

Yugandhara Jirwankar

Akanksha Nair

Soumitra Marathe

Vikas Dighe

Phage Display Identified Novel Leydig Cell Homing Peptides for Testicular Targeting

噬菌体展示鉴定出新型支持细胞归巢肽用于睾丸靶向

Jonas Engelhardt

Anna Klawonn

Ann-Kathrin Dobbelstein

Aliaa Abdelrahman

Johannes Oldenburg

Klaus Brandenburg

Christa E. Müller

Günther Weindl

Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release

脂多糖中和肽调节P2X7受体介导的白细胞介素-1β释放

Heba Ewida

Harrison Benson

Syed Tareq

Mahmoud Salama Ahmed

Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases

分子靶点及小分子化合物在生理与疾病中对乙酰辅酶A的调控作用

Tianyi Wang

Kaiqi Long

Yang Zhou

Xiaoding Jiang

Jinzhao Liu

John H.C. Fong

Alan S.L. Wong

Wai-Lung Ng

Weiping Wang

Correction to “Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy”

“Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy”一文的勘误

Antibody-drug conjugates (ADCs) are a promising drug modality substantially expanding in both the discovery space and clinical development. Assessing the biotransformation of ADCs in vitro and in vivo is important in understanding their stability and pharmacokinetic properties. We previously reported biotransformation pathways for the anti-B7H4 topoisomerase I inhibitor ADC, AZD8205, puxitatug samrotecan, that underpin its structural stability in vivo using an intact protein liquid chromatography-high resolution mass spectrometry (LC-HRMS) approach. Herein, we employed a LC-high resolution multiple reaction monitoring (LC-MRMHR) approach using both collision-induced dissociation (CID) and electron-activated dissociation (EAD) methods, confirming our earlier findings. Furthermore, we were able to obtain additional detailed structural information on the biotransformation products expanding on earlier intact analyses. We also highlight the high sensitivity of LC-MRMHR for successfully identifying minor biotransformation products at low concentrations that were not detectable using the intact protein LC-HRMS workflow. Especially, EAD aided in the confirmation of biotransformation species that contain newly formed disulfide bonds due to the preferential dissociation of disulfide bonds using this method. We observed biotransformation reactions that vary between linker-payload (PL) conjugation sites on the antibody. For example, the trend toward constitutional isomerism in thio-succinimide linker hydrolysis, and the resulting positional isomers from thiol adduct formation following linker-PL deconjugation. The reported orthogonal analytical approaches highly complement and fortify the intact protein LC-HRMS data. This study sheds further light on detailed structural characterization of various ADC species and validates the proposed biotransformation pathways explaining the stability of AZD8205 in vivo.

Junyan Yang

Hui Yin Tan

Jiaqi Yuan

Yue Huang

Anton I. Rosenbaum

Detailed Structural Elucidation of Antibody-Drug Conjugate Biotransformation Species Using High Resolution Multiple Reaction Monitoring Mass Spectrometry with Orthogonal Dissociation Methods

使用正交解离方法的高分辨率多反应监测质谱法对抗体药物偶联物生物转化物种的详细结构阐明

The 26S proteasome degrades the majority of cellular proteins and affects all aspects of cellular life. Therefore, the 26S proteasome abundance, proper assembly, and activity in different life contexts need to be precisely controlled. Impaired proteasome activity is considered a causative factor in several serious disorders. Recent advances in proteasome biology have revealed that the proteasome can be activated by different factors or small molecules. Thus, activated ubiquitin-dependent proteasome degradation has effects such as extending the lifespan in different models, preventing the accumulation of protein aggregates, and reducing their negative impact on cells. Increased 26S proteasome-mediated degradation reduces proteotoxic stress and can potentially improve the efficacy of engineered degraders, such as PROTACs, particularly in situations characterized by proteasome malfunction. Here, emerging ideas and recent insights into the pharmacological activation of the proteasome at the transcriptional and posttranslational levels are summarized.

Jindrich Sedlacek

Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs

26S蛋白酶体的激活以减少蛋白质毒性应激并提高PROTACs的疗效

Abbreviation	ACS Pharmacol. Transl. Sci.
Journal Impact	4.90
Quartiles(Global)	PHARMACOLOGY & PHARMACY(Q1)

ISSN	2575-9108
h-index	36

Publication Information	Publisher: American Chemical Society，Publishing cycle: ，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 2018，Proportion of original research papers: ，Self Citation Rate:， Gold OA Rate: 11.82

ACS Pharmacology and Translational Science

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Novel and Structurally Diversified Bacterial DNA Gyrase Inhibitors Discovered through a Fluorescence-Based High-Throughput Screening Assay

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

Updates on Overcoming Bicalutamide Resistance: A Glimpse into Resistance to a Novel Antiandrogen

Phage Display Identified Novel Leydig Cell Homing Peptides for Testicular Targeting

Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release

Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release

Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases

Correction to “Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy”

Detailed Structural Elucidation of Antibody-Drug Conjugate Biotransformation Species Using High Resolution Multiple Reaction Monitoring Mass Spectrometry with Orthogonal Dissociation Methods

Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs