Search Our Scientific Publications & Authors

ACS Chem Biol 2022 May 26. Epub 2022 May 26.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Postgenomic analysis manifested that filamentous fungi contain numerous natural product biosynthetic gene clusters in their genome, yet most clusters remain cryptic or down-regulated. Herein, we report the successful manipulation of strain sp. CPCC 400735 that enables its genetic engineering via targeted overexpression of pathway-specific transcriptional regulator AspE. Read More

ACS Chem Biol 2022 May 25. Epub 2022 May 25.

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada.

A comprehensive analysis of the phosphoproteome is essential for understanding molecular mechanisms of human diseases. However, current tools used to enrich phosphotyrosine (pTyr) are limited in their applicability and scope. Here, we engineered new superbinder Src-Homology 2 (SH2) domains that enrich diverse sets of pTyr-peptides. Read More

ACS Chem Biol 2022 May 25. Epub 2022 May 25.

Department of Physics, Syracuse University, 201 Physics Building, Syracuse, New York 13244-1130, United States.

Progress in tumor sequencing and cancer databases has created an enormous amount of information that scientists struggle to sift through. While several research groups have created computational methods to analyze these databases, much work still remains in distinguishing key implications of pathogenic mutations. Here, we describe an approach to identify and evaluate somatic cancer mutations of WD40 repeat protein 5 (WDR5), a chromatin-associated protein hub. Read More

ACS Chem Biol 2022 May 25. Epub 2022 May 25.

Department of Cancer Systems Imaging, MD Anderson Cancer Center, Houston, Texas 77054, United States.

Therapeutic monoclonal antibodies directed against PD-L1 (e.g., atezolizumab) disrupt PD-L1:PD-1 signaling and reactivate exhausted cytotoxic T-cells in the tumor compartment. Read More

ACS Chem Biol 2022 May 25. Epub 2022 May 25.

Fluorescent Zn sensors play a pivotal role in zinc biology, but their application in complex media such as blood serum or plate reader-based cellular assays is hampered by autofluorescence and light scattering. Bioluminescent sensor proteins provide an attractive alternative to fluorescent sensors for these applications, but the only bioluminescent sensor protein developed so far, BLZinCh, has a limited sensor response and a suboptimal Zn affinity. In this work, we expanded the toolbox of bioluminescent Zn sensors by developing two new sensor families that show a large change in the emission ratio and cover a range of physiologically relevant Zn affinities. Read More

ACS Chem Biol 2022 May 24. Epub 2022 May 24.

Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan.

Site-specific chemical modification of mRNA can improve its translational efficiency and stability. For this purpose, it is desirable to develop a complete chemical synthesis method for chemically modified mRNA. The key is a chemical reaction that introduces a cap structure into the chemically synthesized RNA. Read More

ACS Chem Biol 2022 May 24. Epub 2022 May 24.

Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France.

Cell-penetrating peptides cross cell membranes through various parallel internalization pathways. Herein, we analyze the role of the negatively charged lipid phosphatidylinositol-4,5-bisphosphate (PI(4,5)P) in the internalization of Penetratin. Contributions of both inner leaflet and outer leaflet pools of PI(4,5)P were revealed by quantifying the internalization of Penetratin in cells treated with PI(4,5)P binders. Read More

ACS Chem Biol 2022 May 23. Epub 2022 May 23.

Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, Karnataka, India.

Aberrations in glycan and lectin expression and function represent one of the earliest hallmarks of cancer. Among galectins, a conserved family of β-galactoside-binding lectins, the role of Galectin-9 in immune-tumor interactions is well-established, although its effect on cancer cell behavior remains unclear. In this study, we assayed for, and observed, an association between Galectin-9 expression and invasiveness of breast cancer cells and . Read More

ACS Chem Biol 2022 May 22. Epub 2022 May 22.

Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland.

Here we discuss "hidden variables", which are typically introduced during an experiment as a consequence of the application of two independent variables together to create a stimulus. With increased sophistication in modern chemical biology tools and related precision interrogation techniques, hidden variables have become integral to many chemical biologists' routine experiments. For instance, they can appear in the use of light-activatable chemical probes (e. Read More

ACS Chem Biol 2022 May 20. Epub 2022 May 20.

Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States.

Installation of methyl groups can significantly improve the binding of small-molecule drugs to protein targets; however, site-selective methylation often presents a significant synthetic challenge. Metal- and -adenosyl-methionine (SAM)-dependent methyltransferases (MTs) in natural-product biosynthetic pathways are powerful enzymatic tools for selective or chemically challenging C-methylation reactions. Each of these MTs selectively catalyzes one or two methyl transfer reactions. Read More

ACS Chem Biol 2022 May 20. Epub 2022 May 20.

Department of Chemistry, Duke University, 124 Science Drive, Durham, North Carolina 27705, United States.

Discoveries of RNA roles in cellular physiology and pathology are increasing the need for new tools that modulate the structure and function of these biomolecules, and small molecules are proving useful. In 2017, we curated the NA-targeted oactive ligad atabase (R-BIND) and discovered distinguishing physicochemical properties of RNA-targeting ligands, leading us to propose the existence of an "RNA-privileged" chemical space. Biennial updates of the database and the establishment of a website platform (rbind. Read More

ACS Chem Biol 2022 May 20. Epub 2022 May 20.

Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States.

The conversion of -methyladenosine (mA) to -methyladenosine (mA) on RNA is an important step for both allowing efficient reverse transcription read-though for sequencing analysis and mapping modifications in the transcriptome. Enzymatic transformation is often used, but the efficiency of the removal can depend on local sequence context. Chemical conversion through the application of the Dimroth rearrangement, in which mA rearranges into mA under heat and alkaline conditions, is an alternative, but the required alkaline conditions result in significant RNA degradation by hydrolysis of the phosphodiester backbone. Read More

ACS Chem Biol 2022 May;17(5):1011-1012

Department of Genome Sciences, University of Washington, William H. Foege Hall, 3720 15th Ave NE, Seattle, Washington 98195, United States.

ACS Chem Biol 2022 May 19. Epub 2022 May 19.

Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, California 94158, United States.

Covalent inhibitors are viable therapeutics. However, off-target reactivity challenges the field. Chemists have attempted to solve this issue by varying the reactivity attributes of electrophilic warheads. Read More

ACS Chem Biol 2022 May 18. Epub 2022 May 18.

Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada.

With resistance to current agricultural fungicides rising, a great need has emerged for new antifungals with unexploited targets. In response, we report a novel series of diazaborines with potent activity against representative fungal plant pathogens. To identify their mode of action, we selected for resistant isolates using the model fungus . Read More

ACS Chem Biol 2022 May 18. Epub 2022 May 18.

Department of Chemical Biology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.

Fluorescence lifetime multiplexing requires fluorescent probes with distinct fluorescence lifetimes but similar spectral properties. Even though synthetic probes for many cellular targets are available for multicolor live-cell fluorescence microscopy, few of them have been characterized for their use in fluorescence lifetime multiplexing. Here, we demonstrate that, from a panel of 18 synthetic probes, eight pairwise combinations are suitable for fluorescence lifetime multiplexing in living mammalian cell lines. Read More

ACS Chem Biol 2022 May 17. Epub 2022 May 17.

Drug Discovery Science & Technology, AbbVie Inc., North Chicago, Illinois 60064, United States.

Interleukin-1 receptor-associated kinase 3 (IRAK3) is a pseudokinase mediator in the human inflammatory pathway, and ablation of its function is associated with enhanced antitumor immunity. Traditionally, pseudokinases have eluded "druggability" and have not been considered tractable targets in the pharmaceutical industry. Herein we disclose a CRISPR/Cas9-mediated knockout of IRAK3 in monocyte-derived dendritic cells that results in an increase in IL-12 production upon lipopolysaccharide (LPS) stimulation. Read More

ACS Chem Biol 2022 May 16. Epub 2022 May 16.

Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Pasteura 5, Warsaw 02-093, Poland.

Vaccinia virus (VACV) represents a family of poxviruses, which possess their own decapping machinery as a part of their strategy to eliminate host mRNAs and evade the innate immune response. D9 is one of the two encoded VACV decapping enzymes that is responsible for cap removal from the 5' end of both host mRNA transcripts and viral double-stranded RNAs. Little is known about the structural requirements for D9 inhibition by small molecules. Read More

ACS Chem Biol 2022 May 15. Epub 2022 May 15.

TEGA Therapeutics, Inc., 3550 General Atomics Court, G02-102, San Diego, California 92121, United States.

Glycosaminoglycans (GAGs) are a class of highly negatively charged membrane-associated and extracellular matrix polysaccharides involved in the regulation of myriad biological functions, including cell adhesion, migration, signaling, and differentiation, among others. GAGs are typically attached to core proteins, termed proteoglycans (PGs), and can engage >500 binding proteins, making them prominent relays for sensing external stimuli and transducing cellular responses. However, their unique substructural protein-recognition domains that confer their binding specificity remain elusive. Read More

ACS Chem Biol 2022 May 10. Epub 2022 May 10.

Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.

Lectins, carbohydrate-binding proteins of nonimmune origin, bind to carbohydrates and glycan shields present on the surfaces of cells and viral spike proteins. Lectins thus hold great promise as therapeutic and diagnostic proteins, exemplified by their potent antiviral activities and the desire to engineer synthetic carbohydrate receptors based on lectin recognition principles. Here, we describe a new carbohydrate-binding architectural motif─namely, a -symmetric tyrosine-based aromatic core, present in the therapeutic lectin griffithsin (GRFT). Read More

ACS Chem Biol 2022 May 9;17(5):1051-1060. Epub 2022 May 9.

Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal 462066, India.

The introduction of non-natural amino acids into proteins through the stop codon readthrough methodology has been used to design proteins for diverse applications. However, this method suffers from low yields of the modified protein, as the suppressor tRNA that recognizes the stop codon is unable to compete effectively with release factor 1 (RF1), which terminates translation. We reasoned that a suppressor tRNA with improved interaction with the UAG stop codon on the mRNA will be able to compete more effectively with RF1. Read More

ACS Chem Biol 2022 May 6;17(5):1269-1281. Epub 2022 May 6.

Department of Medicine, McMaster Immunology Research Center, Center for Discovery in Cancer Research, Hamilton, Ontario L8S 4K1, Canada.

Covalent antibody recruiting molecules (cARMs) constitute a proximity-inducing chemical strategy to modulate the recognition and elimination of cancer cells by the immune system. Recognition is achieved through synthetic bifunctional molecules that use covalency to stably bridge endogenous hapten-specific antibodies like anti-dinitrophenyl (anti-DNP), with tumor antigens on cancer cell surfaces. To recruit these antibodies, cARMs are equipped with the native hapten-binding molecule. Read More

ACS Chem Biol 2022 May 4. Epub 2022 May 4.

Chemical and Biological Therapeutics, Novartis Institutes for BioMedical Research, Basel, 4056, Switzerland.

Unbiased transcriptomic RNA-seq data has provided deep insights into biological processes. However, its impact in drug discovery has been narrow given high costs and low throughput. Proof-of-concept studies with Digital RNA with pertUrbation of Genes (DRUG)-seq demonstrated the potential to address this gap. Read More

ACS Chem Biol 2022 May 2. Epub 2022 May 2.

Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal.

Paramyxoviruses are enveloped viruses harboring a negative-sense RNA genome that must enter the host's cells to replicate. In the case of the parainfluenza virus, the cell entry process starts with the recognition and attachment to target receptors, followed by proteolytic cleavage of the fusion glycoprotein (F) protein, exposing the fusion peptide (FP) region. The FP is responsible for binding to the target membrane, and it is believed to play a crucial role in the fusion process, but the mechanism by which the parainfluenza FP (PIFP) promotes membrane fusion is still unclear. Read More

ACS Chem Biol 2022 May 28;17(5):1103-1110. Epub 2022 Apr 28.

Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.

Disease intervention at the DNA level generally has been avoided because of off-target effects. Recent advances in genome editing technologies using CRISPR-Cas9 have opened a new era in DNA-targeted therapeutic approaches. However, delivery of such systems remains a major challenge. Read More

ACS Chem Biol 2022 May 28;17(5):1061-1072. Epub 2022 Apr 28.

Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe labellisée Ligue "Cell Polarity, Cell Signaling and Cancer", 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France.

Colorectal cancer (CRC), the second cause of death due to cancer worldwide, is a major public health issue. The discovery of new therapeutic targets is thus essential. Pseudokinase PTK7 intervenes in the regulation of the Wnt/β-catenin pathway signaling, in part, through a kinase domain-dependent interaction with the β-catenin protein. Read More

ACS Chem Biol 2022 May 28;17(5):1174-1183. Epub 2022 Apr 28.

Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.

Anandamide or -arachidonoylethanolamine (AEA) is a signaling lipid that modulates neurotransmitter release via activation of the type 1 cannabinoid receptor (CBR) in the brain. Termination of anandamide signaling is thought to be mediated a facilitated cellular reuptake process that utilizes a purported transporter protein. Recently, WOBE437 has been reported as a novel, natural product-based inhibitor of AEA reuptake that is active in cellular and models. Read More

ACS Chem Biol 2022 May 28;17(5):1015-1021. Epub 2022 Apr 28.

Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.

Reconstituting functional transmembrane (TM) proteins into model membranes is challenging due to the difficulty of expressing hydrophobic TM domains, which often require stabilizing detergents that can perturb protein structure and function. Recent model systems solve this problem by linking the soluble domains of membrane proteins to lipids, using noncovalent conjugation. Herein, we test an alternative solution involving the assembly of TM proteins from synthetic TM domains and expressed soluble domains using chemoselective peptide ligation. Read More

ACS Chem Biol 2022 May 28;17(5):1259-1268. Epub 2022 Apr 28.

Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States.

Targeted protein degradation is a promising therapeutic strategy capable of overcoming the limitations of traditional occupancy-based inhibitors. By ablating all of the associated functions of a protein at once, the event-driven pharmacology of degrader technologies has recently enabled the targeting of proteins that have been historically deemed "undruggable". Most degradation strategies utilize the ubiquitin-proteasome system to mediate intracellular target degradation and are thus limited to targeting proteins with cytoplasmic domains. Read More

ACS Chem Biol 2022 May 27;17(5):1197-1206. Epub 2022 Apr 27.

Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States.

Sulfonolipids (SoLs) are a unique class of sphingolipids featuring a sulfonate group compared to other sphingolipids. However, the biological functions and biosynthesis of SoLs in human microbiota have been poorly understood. Here, we report the discovery and isolation of SoLs from a human opportunistic pathogen DSM16776. Read More