Chao Wang

MRC Laboratory of Molecular Biology

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Matthew R. Groves

University of Groningen

Shiqi Peng

Shanghai Jiao Tong University

Alexander Dömlingꝉ

Institute of Technology and Business

Carsten Wrenger

Universidade de São Paulo

Xiaochen Du

University of Groningen

Ming Zhao

Zhejiang Cancer Hospital

Bidong Zhang

University of Groningen

Xiantao Yang

Chengdu Medical College

Fernando de Assis Batista

Institut Pasteur

Ming Zhao

Shanghai Jiao Tong University

Cooperative Institutions

Peking University

University of Groningen

Capital Medical University

Chinese Academy of Sciences

University Medical Center Groningen

University of Chinese Academy of Sciences

Sun Yat-sen University

Central South University

Tianjin Medical University

Universidade de São Paulo

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Discovery of Small-Molecule Allosteric Inhibitors of PfATC as Antimalarials

Journal of the American Chemical Society (2022)

Chao Wang Bidong Zhang Arne Krüger Xiaochen Du Lidia Visser

The discovery and development of new drugs against malaria remain urgent. Aspartate transcarbamoylase (ATC) has been suggested to be a promising target for antimalarial drug development. Here, we describe a series of small-molecule inhibitors of P. falciparum ATC with low nanomolar binding affinities that selectively bind to a previously unreported allosteric pocket, thereby inhibiting ATC activation. We demonstrate that the buried allosteric pocket is located close to the traditional ATC active site and that reported compounds maintain the active site of PfATC in its low substrate affinity/low activity conformation. These compounds inhibit parasite growth in blood stage cultures at single digit micromolar concentrations, whereas limited effects were seen against human normal lymphocytes. To our knowledge, this series represent the first PfATC-specific allosteric inhibitors.

Affinities

10.1021/jacs.2c08128

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Citations (8)

Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein

Journal of Medicinal Chemistry (2021)

Afsaneh Sadremomtaz Zayana M. Al-Dahmani Angel J. Ruiz‐Moreno Alessandra Monti Chao Wang

The SARS-CoV-2 viral spike protein S receptor-binding domain (S-RBD) binds ACE2 on host cells to initiate molecular events, resulting in intracellular release of the viral genome. Therefore, antagonists of this interaction could allow a modality for therapeutic intervention. Peptides can inhibit the S-RBD:ACE2 interaction by interacting with the protein-protein interface. In this study, protein contact atlas data and molecular dynamics simulations were used to locate interaction hotspots on the secondary structure elements α1, α2, α3, β3, and β4 of ACE2. We designed a library of discontinuous peptides based upon a combination of the hotspot interactions, which were synthesized and screened in a bioluminescence-based assay. The peptides demonstrated high efficacy in antagonizing the SARS-CoV-2 S-RBD:ACE2 interaction and were validated by microscale thermophoresis which demonstrated strong binding affinity (∼10 nM) of these peptides to S-RBD. We anticipate that such discontinuous peptides may hold the potential for an efficient therapeutic treatment for COVID-19.

Microscale Thermophoresis

Docking (animal)

10.1021/acs.jmedchem.1c00477

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Citations (31)

Synthesis and thrombolytic activity of fibrinogen fragment related cyclopeptides

Bioorganic & Medicinal Chemistry Letters (2003)

Ming Zhao Na Lin Chao Wang Shiqi Peng

Cyclic peptide

10.1016/s0960-894x(02)01072-7

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Citations (9)

Alkylation of phosphorothioated thrombin binding aptamers improves the selectivity of inhibition of tumor cell proliferation upon anticoagulation

Biochimica et Biophysica Acta (BBA) - General Subjects (2017)

Xiantao Yang Yuejie Zhu Chao Wang Zhu Guan Lihe Zhang

Aptamer

10.1016/j.bbagen.2017.04.002

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Citations (14)

Small‐Molecule Allosteric Inhibitors of Human Aspartate Transcarbamoylase Suppress Proliferation of Bone Osteosarcoma Epithelial Cells

ChemMedChem (2024)

Chao Wang Bidong Zhang Yingying Cong Xiaochen Du Siyao Chen

Aspartate transcarbamoylase (ATC) is the first committed step in de novo pyrimidine biosynthesis in eukaryotes and plants. A potent transition state analog of human ATCase (PALA) has previously been assessed in clinical trials for the treatment of cancer, but was ultimately unsuccessful. Additionally, inhibition of this pathway has been proposed to be a target to suppress cell proliferation in E. coli, the malarial parasite and tuberculosis. In this manuscript we screened a 70-member library of ATC inhibitors developed against the malarial and tubercular ATCases for inhibitors of the human ATC. Four compounds showed low nanomolar inhibition (IC

Druggability

Aspartate carbamoyltransferase

Pyrimidine metabolism

Docking (animal)

10.1002/cmdc.202300688

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An intestinal Trojan horse for gene delivery

Nanoscale (2015)

Haisheng Peng Chao Wang Xiaoyang Xu Chenxu Yu Qun Wang

A novel intestinal “Trojan horse” for potential gene therapy of intestinal disorders.

Trojan horse

10.1039/c4nr06377e

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Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

MicrobiologyOpen (2019)

Fernando de Assis Batista Soraya S. Bosch Sabine Butzloff Sergey Lunev Kamila Anna Meissner

The appearance of multi-drug resistant strains of malaria poses a major challenge to human health and validated drug targets are urgently required. To define a protein's function in vivo and thereby validate it as a drug target, highly specific tools are required that modify protein function with minimal cross-reactivity. While modern genetic approaches often offer the desired level of target specificity, applying these techniques is frequently challenging-particularly in the most dangerous malaria parasite, Plasmodium falciparum. Our hypothesis is that such challenges can be addressed by incorporating mutant proteins within oligomeric protein complexes of the target organism in vivo. In this manuscript, we provide data to support our hypothesis by demonstrating that recombinant expression of mutant proteins within P. falciparum leverages the native protein oligomeric state to influence protein function in vivo, thereby providing a rapid validation of potential drug targets. Our data show that interference with aspartate metabolism in vivo leads to a significant hindrance in parasite survival and strongly suggest that enzymes integral to aspartate metabolism are promising targets for the discovery of novel antimalarials.

Druggability

10.1002/mbo3.779

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Characterization of cysteine sulfinic acid decarboxylase from Tribolium castaneum and its application in the production of β-alanine

Applied Microbiology and Biotechnology (2019)

Zhongmei Liu Wenhui Zheng Wenqi Ye Chao Wang Yu Gao

Alanine

10.1007/s00253-019-10139-z

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Citations (21)

[The effects of H102 on NF-κB signal pathway in brain of transgenic AD mice].

PubMed (2016)

Chao Wang Xiaoyong Yuan Feng-Xian Sun Fang Jiang Shumei Xu

To investigate the effects of β-sheet breaker peptide H102 on NF-κB signal pathway in brain of APP/PS1 double transgenic mice.Thirty 8-week-old APP/PS1 double transgenic mice were randomly divided into model group and treatment group. A group of C57BL/6J mice with the same age and background were served as controls (n=15). H102 5 μl(5.8 mg/kg) was infused by intranasal administration to mice in H102 treatment group, and equal volume of blank solution of H102 (chitosan, BSA) was given to mice in control group and model group. After 16 weeks, the ability of spatial reference memory was tested by Morris Water Maze. Then immunohistochemistry tests and Western blot technique were used to detect the content of amyloid beta peptide 1-42(Aβ1-42), nuclear factor-kappa B (NF-κB), inhibitor of NF-κB (IκB), IκB kinase (IKK), the corresponding phosphorylated proteins (p-NF-κB、p-IκB、p-IKK), inducible nitric oxide synthase (iNOS) and cleaved Caspase 3 proteins in mice brain.①The ability of learning and memory was significantly lowered in model group than that in control group. And the ability of learning and memory was significantly improved in treatment group than that in model group (P<0.05). ②The contents of Aβ1-42, p-IKK, p-NF-κB, p-IκB, intranuclear NF-κB,iNOS and cleaved Caspase 3 in mouse brain were significantly increased in model group than those of control group, and these protein expressions were significantly lowered in treatment group than those in model group (P<0.05).H102 can inhibit NF-κB signal pathway in brain of APP/PS1 double transgenic mice, reduce the levels of inflammation and apoptosis in nerve cells, and improve the ability of learning and memory in transgenic AD mice.

10.13459/j.cnki.cjap.2016.03.001

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The composition and sequence specificity of Pro-Ala-Lys-OH for the thrombolytic activities of P6A and related oligopeptides

Bioorganic & Medicinal Chemistry (2004)

Ming Zhao Chao Wang Jiangyuan Liu Kexiang Zhou Shiqi Peng

Oligopeptide

Sequence (biology)

Structure–activity relationship

10.1016/j.bmc.2004.02.011

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Citations (8)