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8 results on '"Alice Shi Ming Li"'

1. Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity

Author

Mark F. Mabanglo, Brian Wilson, Mahmoud Noureldin, Serah W. Kimani, Ahmed Mamai, Chiara Krausser, Héctor González-Álvarez, Smriti Srivastava, Mohammed Mohammed, Laurent Hoffer, Manuel Chan, Jamie Avrumutsoae, Alice Shi Ming Li, Taraneh Hajian, Sarah Tucker, Stuart Green, Magdalena Szewczyk, Dalia Barsyte-Lovejoy, Vijayaratnam Santhakumar, Suzanne Ackloo, Peter Loppnau, Yanjun Li, Almagul Seitova, Taira Kiyota, Jue George Wang, Gilbert G. Privé, Douglas A. Kuntz, Bhashant Patel, Vaibhavi Rathod, Anand Vala, Bhimsen Rout, Ahmed Aman, Gennady Poda, David Uehling, Jailall Ramnauth, Levon Halabelian, Richard Marcellus, Rima Al-awar, and Masoud Vedadi

Subjects
Science
Abstract

Abstract Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs. We recently developed potent ligands for DCAF1, a substrate receptor of EDVP and CUL4 E3 ligases. Here, we focus on DCAF1 toward the development of PROTACs for WDR5, a drug target in various cancers. We report four DCAF1-based PROTACs with endogenous and exogenous WDR5 degradation effects and high-resolution crystal structures of the ternary complexes of DCAF1-PROTAC-WDR5. The structures reveal detailed insights into the interaction of DCAF1 with various WDR5-PROTACs, indicating a significant role of DCAF1 loops in providing needed surface plasticity, and reflecting the mechanism by which DCAF1 functions as a substrate receptor for E3 ligases with diverse sets of substrates.

Published
2024
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2. Discovery of Nanomolar DCAF1 Small Molecule Ligands

Author

Alice Shi Ming Li, Serah Kimani, Brian Wilson, Mahmoud Noureldin, Héctor González-Álvarez, Ahmed Mamai, Laurent Hoffer, John P. Guilinger, Ying Zhang, Moritz von Rechenberg, Jeremy S. Disch, Christopher J. Mulhern, Belinda L. Slakman, John W. Cuozzo, Aiping Dong, Gennady Poda, Mohammed Mohammed, Punit Saraon, Manish Mittal, Pratik Modh, Vaibhavi Rathod, Bhashant Patel, Suzanne Ackloo, Vijayaratnam Santhakumar, Magdalena M Szewczyk, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Richard Marcellus, Marie-Aude Guié, Anthony D. Keefe, Peter J. Brown, Levon Halabelian, Rima Al-awar, and Masoud Vedadi

Subjects
Drug Discovery, Molecular Medicine
Published
2023
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3. Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors

Author

Haitham Hassan, Jeanne Chiavaralli, Afnan Hassan, Loay Bedda, Tim Krischuns, Kuang-Yu Chen, Alice Shi Ming Li, Adrien Delpal, Etienne Decroly, Masoud Vedadi, Nadia Naffakh, Fabrice Agou, Sergio Mallart, Reem K. Arafa, Paola B. Arimondo, Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Zewail City of Science and Technology, Biologie des ARN et virus influenza - RNA Biology of Influenza Virus (CNRS-UMR3569), University of Toronto, Aix Marseille Université (AMU), Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fondation de France grant Programme Féderateur de Recherche sur SARS-CoV2 & COVID-19 PRF7 SARS-CoV2 drugpipeline project (to PBA). Vedadi's lab is funded by the US NIH 1U19AI171110-01.The 'URGENCE COVID-19' fundraising campaign of Institut Pasteur and by the Agence Nationale de la Recherche (grants ANR-18-CE18-0026, ANR-18-CE18-0028 and ANR-10-LABX-62-IBEID), The authors thank Dr Benjamin BARDIAUX, Structural Bioinformatics Laboratory, Institute Pasteur, for constructive proofreading of the in silico studies part. The authors thank the Institut Pasteur and Fondation de France grants for the installation and the Drug pipeline against SARS-CoV-2 project. Sylvain Paisant and Marine Ghazarian are acknowledged for providing technical help for the Mpro cell-based assay., ANR-18-CE18-0026,microFLU-REASSORT,Analyse à haut-débit du réassortiment entre virus influenza A par microfluidique et séquençage du génome ARN de virus uniques - application à l'analyse du risque pandémique et à l'optimisation des virus candidats vaccins(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Pharmacology, [SDV]Life Sciences [q-bio], Organic Chemistry, Drug Discovery, Pharmaceutical Science, Molecular Medicine, Biochemistry
Abstract

International audience; A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural product likeness proved to have antiviral activity against SARS-CoV-2.

Published
2023
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4. Rational design of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors

Author

Milan Stefek, Dominika Chalupska, Karel Chalupsky, Michala Zgarbova, Alexandra Dvorakova, Petra Krafcikova, Alice Shi Ming Li, Michal Sala, Milan Dejmek, Tomas Otava, Ema Chaloupecka, Masoud Vedadi, Jan Weber, Helena Mertlikova-Kaiserova, and Radim Nencka

Abstract

The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in current medicinal chemistry. Targeting capping machinery could be one of therapeutic concepts based on a unique mechanism of action. Viral RNA cap synthesis involves two methylation steps, the first of which is mediated by the nsp14 protein. Here, we rationally designed and synthesized a series of compounds capable of binding to both the S-adenosyl-L-methionine and the RNA binding site of SARS-CoV-2 nsp14 7-N methyltransferase. These hybrid molecules exerted excellent potency, high selectivity towards various human methyltransferases, they are nontoxic and highly cell permeable. Despite the outstanding activity against the enzyme, our compounds showed poor antiviral performance in vitro. This suggests that the activity of this viral methyltransferase is mainly associated with immune response. Our compounds represent unique tools to further explore the role of the SARS-CoV-2 nsp14 methyltransferase in viral replication.

Published
2023
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8. Chemical probes for protein arginine methyltransferases

Author

Masoud Vedadi, Carlo C. dela Seña, Fengling Li, Alice Shi Ming Li, Mohammad S. Eram, and Albina Bolotokova

Subjects
Protein-Arginine N-Methyltransferases, S-Adenosylmethionine, Methyltransferase, Arginine, Chemical probe, Peptide, General Biochemistry, Genetics and Molecular Biology, Histones, 03 medical and health sciences, Transcription (biology), Neoplasms, Humans, Enzyme Inhibitors, Molecular Biology, Phylogeny, 030304 developmental biology, Cell Proliferation, Enzyme Assays, chemistry.chemical_classification, 0303 health sciences, Chemistry, F-Box Proteins, 030302 biochemistry & molecular biology, DNA Damage Repair, Kinetics, Biochemistry, RNA Splicing Factors, Methyl donor
Abstract

Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups to specific arginine residues of their substrates using S-adenosylmethionine as a methyl donor, contributing to regulation of many biological processes including transcription, and DNA damage repair. Dysregulation of PRMT expression is often associated with various diseases including cancers. Different methods have been used to characterize the activities of PRMTs and determine their kinetic parameters including mass spectrometry, radiometric, and antibody-based assays. Here, we present kinetic characterization of PRMTs using a radioactivity-based assay for better comparison along with previously reported values. We also report on full characterization of PRMT9 activity with SAP145 peptide as substrate. We further review the potent, selective and cell-active PRMT inhibitors discovered in recent years to provide a better understanding of available tools to investigate the roles these proteins play in health and disease.

Published
2019

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