Article
Microbiology
Dirk Jochmans, Cheng Liu, Kim Donckers, Antitsa Stoycheva, Sandro Boland, Sarah K. Stevens, Chloe De Vita, Bert Vanmechelen, Piet Maes, Bettina Trueb, Nadine Ebert, Volker Thiel, Steven De Jonghe, Laura Vangeel, Dorothee Bardiot, Andreas Jekle, Lawrence M. Blatt, Leonid Beigelman, Julian A. Symons, Pierre Raboisson, Patrick Chaltin, Arnaud Marchand, Johan Neyts, Jerome Deval, Koen Vandyck
Summary: Paxlovid is the first oral antiviral approved for the treatment of SARS-CoV-2 infection. Research has identified mutations in the 3CLpro protease that may lead to resistance against Paxlovid. These findings are important for guiding the use of novel antiviral drugs.
Article
Chemistry, Multidisciplinary
Lifeng Sun, Pradeep Chopra, Geert-Jan Boons
Summary: A new method for the synthesis of heparan sulfate oligosaccharides composed of unsulfonated fragments of different lengths was reported. Competition binding studies showed that the length of the unsulfonated fragment modulates the binding of chemokines.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Medicinal
Arun K. Ghosh, Satish Kovela, Ashish Sharma, Dana Shahabi, Ajay K. Ghosh, Denver R. Hopkins, Monika Yadav, Megan E. Johnson, Johnson Agniswamy, Yuan-Fang Wang, Shin-Ichiro Hattori, Nobuyo Higashi-Kuwata, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya
Summary: This study reports the design, synthesis, X-ray structural analysis, and biological evaluation of highly potent HIV-1 protease inhibitors. The inhibitors combine a novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands with various P1 and P2' ligands. The inhibitor with difluoromethylphenyl P1 ligand and cyclopropylaminobenzothiazole P2' ligand demonstrates the most potent antiviral activity, including against highly multidrug-resistant HIV-1 variants. Two high-resolution X-ray structures of inhibitor-bound HIV-1 protease provide molecular insight.
Article
Multidisciplinary Sciences
Chih-Lan Lin, Mirat Sojitra, Eric J. Carpenter, Ellen S. Hayhoe, Susmita Sarkar, Elizabeth A. Volker, Chao Wang, Duong T. Bui, Loretta Yang, John S. Klassen, Peng Wu, Matthew S. Macauley, Todd L. Lowary, Ratmir Derda
Summary: This study demonstrates the chemoenzymatic synthesis of a genetically-encoded liquid glycan array (LiGA) of complex type N-glycans on phage. The LiGA facilitates rigorous characterization of N-glycan structure and density using MALDI-TOF MS, and enables the identification of optimal structure/density combinations for recognition by glycan-binding proteins (GBPs). Injection of the LiGA into mice also helps identify glycoconjugates with structures and avidity necessary for enrichment in specific organs.
NATURE COMMUNICATIONS
(2023)
Article
Microbiology
Paulina Koszalka, Ankita George, Vijaykrishna Dhanasekaran, Aeron C. Hurt, Kanta Subbarao
Summary: Combination therapy with influenza drugs baloxavir and oseltamivir can reduce the selection of viruses with reduced drug susceptibility. In animal models, combination therapy and monotherapy have similar effectiveness in reducing viral titers, but combination therapy can decrease the selection of viruses with reduced susceptibility to baloxavir.
Article
Chemistry, Applied
Paul S. Riehl, Jesmine Lim, James D. Finnigan, Simon J. Charnock, Todd K. Hyster
Summary: In this study, a chemoenzymatic synthesis method for the bicyclic fragment of Darunavir is described. A ketoreductase was identified using metagenomic mining to catalyze a highly enantio- and diastereoselective dynamic kinetic resolution of a beta-ketolactone. The bicyclic acetal fragment was obtained in 39% yield over four steps using diisobutylaluminum hydride and phase transfer cyclization.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Review
Chemistry, Organic
Hui-Jing Wang, Yang-Yang Zhong, You-Cai Xiao, Fen-Er Chen
Summary: This review summarizes the historical perspective and recent advances in the stereoselective synthesis of beta-nucleosides and their analogues, and introduces three synthetic strategies.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Chemistry, Analytical
Xing Zhang, Caiyi Zhang, Na Li, Wenzhen Pan, Mengying Fu, Jeremiah Ong'achwa Machuki, Kezhen Ge, Zhao Liu, Fenglei Gao
Summary: The study introduces a versatile nanoprobe APT that combines FRET and oxygen-augmenting strategy, enabling glycosylation detection, O-2 self-sufficiency, and collaborative phototherapy, showing significant therapeutic advantages against hypoxic tumors.
ANALYTICAL CHEMISTRY
(2021)
Article
Chemistry, Organic
Zhuojia Xu, Yaqi Deng, Zhumin Zhang, Wenjing Ma, Wanjin Li, Liuqing Wen, Tiehai Li
Summary: A diversity-oriented chemoenzymatic approach was used for the collective preparation of sulfated core 2 O-GalNAc glycans and their nonsulfated counterparts. A sulfated trisaccharide and a nonsulfated trisaccharide were chemically synthesized, then enzymatic extension was carried out using a panel of robust glycosyltransferases to achieve regioselective sialylation, resulting in the generation of 36 structurally well-defined O-GalNAc glycans.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Kai-Eng Ooi, Xiu-Wen Zhang, Cheng-Yu Kuo, Ying-Jia Liu, Ching-Ching Yu
Summary: We reported the first chemoenzymatic synthesis of lacto-N-hexaose (LNH) by combining chemical carbohydrate synthesis with a selectively enzymatic glycosylation strategy. Lacto-N-neotetraose (LNnH) was also synthesized during the process.
FRONTIERS IN CHEMISTRY
(2022)
Article
Microbiology
Aitor Casas-Sanchez, Alessandra Romero-Ramirez, Eleanor Hargreaves, Cameron C. Ellis, Brian Grajeda, Igor L. Estevao, Edward Patterson, Grant L. Hughes, Igor C. Almeida, Tobias Zech, Alvaro Acosta-Serrano
Summary: The study demonstrates that interfering with the N-glycosylation of spike proteins can significantly reduce the spread of SARS-CoV-2 infection, including various variants. As new SARS-CoV-2 variants with different levels of resistance against current vaccines are likely to appear, targeting the virus glycosylation using approved human drugs could be a complementary strategy to reduce the global spread of COVID-19.
Article
Chemistry, Organic
Shiwei Luo, Yating Liu, Tianhui Hao, Wenjing Ma, Yawen Luo, Shasha Wang, Zhuojia Xu, Chaoyu Hu, Liuqing Wen, Tiehai Li
Summary: The first total synthesis of Haemophilus ducreyi lipooligosaccharide core octasaccharides containing natural and unnatural sialic acids has been achieved by an efficient chemo-enzymatic approach. Key features include the development of a highly convergent [3 + 3] coupling strategy for assembling the hexasaccharide core and the successful introduction of a galactose residue and different sialic acids using sequential enzyme-catalyzed reactions.
Article
Chemistry, Organic
Beata Zdun, Tamara Reiter, Wolfgang Kroutil, Pawel Borowiecki
Summary: We developed chemoenzymatic routes using low-cost starting materials and enzyme preparations to synthesize tenofovir. The key step involved stereoselective reduction or kinetic resolution using alcohol dehydrogenase or lipase as biocatalysts. By employing immobilized lipase in a mixture of vinyl acetate and toluene, the desired (R)-ester was obtained with high yield and optical purity. Alternatively, reduction of a ketone using lyophilized E. coli cells containing recombinant alcohol dehydrogenase resulted in excellent conversion and yield of the corresponding (R)-alcohol. The enzymatic strategy could be applied in the synthesis of tenofovir prodrug derivatives.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Yinping Tian, Qiang Zhu, Zeyu Sun, Didi Geng, Bingyi Lin, Xiaoling Su, Jiahui He, Miao Guo, Hong Xu, Ye Zhao, Weijie Qin, Peng George Wang, Liuqing Wen, Wen Yi
Summary: This study identifies a novel O-GlcNAcylated protein and reveals its regulatory role in cell cycle progression and DNA damage response.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Stella Scholz, Sofia Kerestetzopoulou, Vincent Wiebach, Romina Schnegotzki, Bianca Schmid, Emmanuel Reyna-Gonzalez, Ling Ding, Roderich D. Sussmuth, Elke Dittmann, Martin Baunach
Summary: In this study, a chemoenzymatic in vitro platform was used to introduce functional tags in various microviridin variants, resulting in biotinylated, dansylated, or propargylated congeners. This direct approach provides a pathway for the development of customized protease inhibitors with built-in functionalities.
Review
Chemistry, Multidisciplinary
Daan Sondag, Stijn Verhoeven, Dennis W. P. M. Lowik, Mark van Geffen, Cornelis van't Veer, Waander L. van Heerde, Thomas J. Boltje, Floris P. J. T. Rutjes
Summary: The blood coagulation cascade is a complex process involving multiple enzymes, cofactors, and substrates, and its dysregulation can lead to bleeding disorders and thrombosis. This review summarizes the key proteases involved in blood clot formation and fibrinolysis, their recognition and hydrolysis of endogenous peptide sequences, and the use of synthetic peptide probes for measuring their activity. The information provided in this review can contribute to the development of novel anticoagulant therapies and specific substrates for point-of-care diagnosis of coagulation pathologies.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Medicinal
Bo Liu, Xueni Yu, Liping Liu, Lei Wang, Jie Wang, Qianqian Huang, Zhongliang Xu, Cheng Luo, Liguang Lou, Wei Huang, Weibo Yang
Summary: This study presents a modular biomimetic strategy for the efficient synthesis of a new class of macrocycles with polysubstituted 1,3-diene, which exhibit potent inhibition of P-gp and reversal of multidrug resistance. Structure-activity relationship analysis reveals that the size and linker of the macrocycles are crucial for restoring activity. Compound 32, containing a naphthyl group and (D)-Phe moiety, exhibits higher potency than verapamil and induces conformational change of P-gp to inhibit its function. Compounds 23 and 32 are identified as attractive leads, showing good pharmacokinetic profile and antitumor activity in a KBV200 xenograft mouse model.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Wei Shi, Jianxin Zhang, Liya Liu, Wanzhen Li, Zhi Liu, Anni Ren, Jie Wang, Caihong Tang, Yang Yang, Dandan Xu, Qianqian Huang, Yongqin Wang, Caili Luo, Wei Huang, Feng Tang
Summary: The inadequate understanding of the structure-activity relationship (SAR) of glycosite-specific antibody-drug conjugates (ADCs) hinders its design and development. In this study, we constructed and examined 50 gsADC structures with various glycan subtypes and linker-drug combinations to reveal the systematic SAR and structure-toxicity relationship (STR) of gsADCs. Our findings suggest that the use of extra hydrophilic linkers is crucial for intact glycan-based gsADCs to improve in vivo efficacy. Additionally, gsADCs that conjugate linker-drug complexes onto the terminal sialic acid demonstrate greater stability and potency compared to those conjugated onto the terminal galactose. Moreover, LacNAc-based gsADCs, which adopt a shorter spacer and locate the linker-drug more inside the immunoglobulin class G (IgG) Fc cavity, exhibit excellent hydrophilicity, in vivo activity, pharmacokinetics, and safety. Overall, we found that concealing the linker-toxin within the Fc cavity can significantly enhance the therapeutic index of LacNAc-based gsADCs, facilitating the design of ADCs with optimal druggability.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Lennart Dreisewerd, Ruud L. E. G. Aspers, Martin C. Feiters, Floris P. J. T. Rutjes, Marco Tessari
Summary: Differentiating and quantifying enantiomers is crucial in pharmaceutical, chemical, and food industries. However, traditional methods are time-consuming and require complex techniques and expertise. We propose a new approach using non-hydrogenative parahydrogen-induced hyperpolarization and nuclear magnetic resonance, which allows for direct detection, discrimination, and quantification of enantiomers in complex mixtures like biofluids and food extracts, without the need for prior isolation or functionalization.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Review
Biochemistry & Molecular Biology
Qixiong Lu, Xiaoyang Lu, Yuansheng Zhang, Wei Huang, Hu Zhou, Tao Li
Summary: Ferroptosis is a form of cell death characterized by excessive iron-dependent lipid peroxidation. It disrupts the cellular antioxidant capacities and leads to oxidative overload and cell death. Ferroptosis plays a significant role in various diseases.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Review
Chemistry, Multidisciplinary
Daan Sondag, Stijn Verhoeven, Dennis W. P. M. Lowik, Mark van Geffen, Cornelis van't Veer, Waander L. van Heerde, Thomas J. Boltje, Floris P. J. T. Rutjes
Summary: The blood coagulation cascade is a complex physiological process that involves multiple enzymes, cofactors, and substrates, leading to clot formation. Serine proteases play a crucial role, and abnormalities in their activity can result in life-threatening bleeding disorders and thrombosis. This review summarizes the important proteases involved in blood coagulation and fibrinolysis, their recognition and hydrolysis of endogenous peptide sequences, and synthetic peptide probes for measuring their activity. The information in this review can contribute to the development of novel anticoagulant therapies and specific substrates for point-of-care diagnosis of coagulation pathologies.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Medicinal
Dongliang Guan, Feifei Chen, Wei Shi, Lefu Lan, Wei Huang
Summary: The authors synthesized 40 novel norvancomycin derivatives, of which 32 were single N-terminally modified derivatives obtained through simple and efficient methods. The diverse N-terminal modifications were mainly achieved by lipophilic attachment and introduction of lipo-sulfonium moieties for extensive structure-activity relationship analysis. The first incorporation of a sulfonium moiety into the norvancomycin structure resulted in compounds with 4- to 2048-fold higher activity against vancomycin-resistant bacteria VISA and VRE. This N-terminal modification for norvancomycin provides a useful and promising strategy to restore the antibacterial activity of glycopeptide antibiotics against resistant bacteria, highlighting the same importance of the N-terminal site as well as the vancosamine position, which deserves further study and development.
Review
Chemistry, Organic
Stefan van Rootselaar, Evert Peterse, Daniel Blanco-Ania, Floris P. J. T. Rutjes
Summary: Piperidine alkaloids are a type of alkaloid characterized by a six-membered nitrogen-containing heterocycle. They are mainly found in plants and have interesting biological and pharmacological activities. The synthesis of piperidine alkaloids and their derivatives is important for drug discovery due to their low natural abundance.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Biochemical Research Methods
Miloslav Sanda, Yang Qiang, Zong Guanghui, Chen He, Zheng Zhihao, Harmeet Dhani, Khalid Khan, Alexander Kroemer, Wang Lai-Xi, Radoslav Goldman
Summary: Targeted quantification of glycoproteins has been limited by the lack of optimized workflows and isotopically labeled standards. In this study, a streamlined chemoenzymatic synthesis of isotopically labeled glycopeptides of IgG1 was introduced for quantification in an energy optimized LC-MS/MS-PRM workflow. The incorporation of stable isotope labeled N-acetylglucosamine enabled efficient monitoring of glycopeptide fragment ions, resulting in reduced quantification variability and higher sensitivity compared to traditional workflows. Rapid quantification of IgG1 Fc glycoforms from COVID-19 patients was successfully demonstrated.
JOURNAL OF PROTEOME RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Haihua He, Chonglai Chen, Chaoqun Bian, Junhua Ren, Jiajia Liu, Wei Huang
Summary: Ammonia decomposition is a promising method for high-purity hydrogen production, but it typically requires precious metals as catalysts. This study proposes using Ni/GdxCe1-xO2-delta catalysts to improve performance by adjusting support properties and investigates the underlying mechanism. It is found that Ni/Ce0.8Gd0.2O2-delta exhibits high catalytic activity and stability due to a high concentration of oxygen vacancies, highly dispersed Ni, and abundant strong basic sites.
Article
Chemistry, Medicinal
Tom Dekker, Mathilde A. C. H. Janssen, Christina Sutherland, Rene W. M. Aben, Hans W. Scheeren, Daniel Blanco-Ania, Floris P. J. T. Rutjes, Maikel Wijtmans, Iwan J. P. de Esch
Summary: The success of fragment-based drug discovery (FBDD) is closely related to library design. A workflow in KNIME software has been created to guide the design of fragment libraries, considering chemical diversity and novelty of the fragments, as well as their three-dimensional (3D) character. This design tool can create large and diverse libraries or select representative compounds to enrich existing libraries.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Wei Huang, Yuliang Wu, Jihui Zhu, Ning Luo, Chunyan Wang, Shupeng Liu, Zhongping Cheng
Summary: This study investigated the expression features of FDX1 in tumors and its correlations with prognosis, tumor stages, immune microenvironment, and cuproptosis from a pan-cancer perspective based on integrated bioinformatics. The results showed that FDX1 was abnormally expressed in multiple tumor types and demonstrated variability in various tumor stages. It predicted poor prognosis in glioma (GBMLGG) and brain lower-grade glioma (LGG), and good prognosis in kidney renal clear cell carcinoma (KIRC). FDX1 showed positive correlations to StromalScore, ImmuneScore, ESTIMATEScore in LGG and negative correlation in KIRC. High expression of FDX1 was accompanied by high expression of immune checkpoints such as CD276 (B7-H3), CD274 (PD-L1), PDCD1LG2 (PD-L2), CTLA4, and HAVCR2 in LGG.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Thomas C. Donahue, Chong Ou, Qiang Yang, Robin Flinko, Xiao Zhang, Guanghui Zong, George K. Lewis, Lai-Xi Wang
Summary: Targeted degradation using cell-specific lysosome targeting receptors is a new therapeutic strategy for eliminating disease-associated proteins. This study focuses on using the liver-specific human asialoglycoprotein receptor (ASGPR) for targeted protein degradation (TPD). The efficiency of different glycan ligands for ASGPR-mediated lysosomal delivery is investigated, and chemoenzymatic Fc glycan remodeling is employed for constructing antibody-ligand conjugates. The results show that the nature of the glycan ligands and the spacer length in the conjugates are critical for receptor binding and degradation of disease-associated proteins.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Analytical
Diana Campos, Michael Girgis, Qiang Yang, Guanghui Zong, Radoslav Goldman, Lai-Xi Wang, Miloslav Sanda
Summary: Mass spectrometry can provide valuable insights into glycosylation analysis, but analyzing isobaric glycopeptide structures remains challenging. Modulating collision energy can improve structural elucidation, especially for qualitative purposes. Our research identified the potential for false-positive structure assignments and established a minimum intensity threshold to prevent misidentification of structure-specific fragments in glycoproteomics analysis.
ANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Inorganic & Nuclear
Mathijs J. Bouma, Ruud L. E. G. Aspers, Marco Tessari, Floris P. J. T. Rutjes, Roan Fraser, Martin C. Feiters
Summary: Non-hydrogenative Para-Hydrogen Induced Hyperpolarization (nhPHIP) is a Nuclear Magnetic Resonance (NMR) hyperpolarization technique that has been used to analyze complex biological samples containing amino acids. A computational study based on Density Function Theory (DFT) was performed to analyze the structures and properties of the relevant catalysts and amino acids. The results provided detailed explanations for the observed trends in thermal NMR experiments.
EUROPEAN JOURNAL OF INORGANIC CHEMISTRY
(2023)
