Cindy Meyer
@rockefeller.edu
Rockefeller University
Scopus Publications
- Discovery, Optimization, and Evaluation of Non-Nucleoside SARS-CoV-2 NSP14 Inhibitors
Michael W. Miller, Cindy Meyer, Aitor Garzia, Hans-Heinrich Hoffmann, Tanweer A. Khan, Melissa Egbertson, Robert W. Myers, Nigel Liverton, Stacia Kargman, Jada A. Davis, Oleg Ganichkin, Julius Nitsche, Stefan Steinbacher, Shlomi Dagan, J. Fraser Glickman, Charles M. Rice, Thomas Tuschl, Peter T. Meinke, David J. Huggins
Journal of Medicinal Chemistry, 2025
We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an antiviral therapeutic. - Discovery of Novel Isofunctional SARS-CoV-2 NSP14 RNA Cap Methyltransferase Inhibitors by Structure-Based Virtual Screening
Cindy Meyer, Mayako Michino, David J. Huggins, Aitor Garzia, Jada A. Davis, Michael W. Miller, Nigel Liverton, Hans-Heinrich Hoffmann, J. Fraser Glickman, Julius Nitsche, Oleg Ganichkin, Stefan Steinbacher, Charles M. Rice, Peter T. Meinke, Thomas Tuschl
ACS Medicinal Chemistry Letters, 2025
High Resolution Image Download MS PowerPoint Slide In early 2020, SARS-CoV-2 spread into a worldwide pandemic, causing more than 7 million deaths. Direct-acting antivirals (DAAs) complementing vaccines and mitigating severe disease in at-risk populations remain important. Here, we used a structure-based virtual screening (SBVS) workflow to identify new SAH-dependent inhibitors of the SARS-CoV-2 RNA cap methyltransferase NSP14. We virtually screened the Enamine and Sigma in-stock screening collections as well as the 3 orders of magnitude larger Enamine REAL make-on-demand compound library, which produced better docking scores and higher virtual hit rates. While biochemical testing of 145 in-stock library compounds yielded a single NSP14-specific inhibitor, 123 chemically synthesized Enamine REAL SBVS compounds contained 10 hits specifically inhibiting NSP14 with half-maximal inhibitory concentrations (IC 50 ) below 10 μM. The new compounds were chemically distinct in atomic composition from any NSP14 inhibitors previously identified by conventional biochemical high-throughput screening (HTS) and may serve as starting points to develop novel SARS-CoV-2 DAAs. - Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
Cindy Meyer, Aitor Garzia, Michael W. Miller, David J. Huggins, Robert W. Myers, Hans-Heinrich Hoffmann, Alison W. Ashbrook, Syeda Y. Jannath, Nigel Liverton, Stacia Kargman, Matthew Zimmerman, Andrew M. Nelson, Vijeta Sharma, Enriko Dolgov, Julianna Cangialosi, Suyapa Penalva-Lopez, Nadine Alvarez, Ching-Wen Chang, Neelam Oswal, Irene Gonzalez, Risha Rasheed, Kira Goldgirsh, Jada A. Davis, Lavoisier Ramos-Espiritu, Miriam-Rose Menezes, Chloe Larson, Julius Nitsche, Oleg Ganichkin, Hanan Alwaseem, Henrik Molina, Stefan Steinbacher, J. Fraser Glickman, David S. Perlin, Charles M. Rice, Peter T. Meinke, Thomas Tuschl
Nature, 2025 - In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion
Hasan Vatandaslar, Aitor Garzia, Cindy Meyer, Svenja Godbersen, Laura T. L. Brandt, Esther Griesbach, Jeffrey A. Chao, Thomas Tuschl, Markus Stoffel
Nature Communications, 2023
System-wide cross-linking and immunoprecipitation (CLIP) approaches have unveiled regulatory mechanisms of RNA-binding proteins (RBPs) mainly in cultured cells due to limitations in the cross-linking efficiency of tissues. Here, we describe viP-CLIP (in vivo PAR-CLIP), a method capable of identifying RBP targets in mammalian tissues, thereby facilitating the functional analysis of RBP-regulatory networks in vivo. We applied viP-CLIP to mouse livers and identified Insig2 and ApoB as prominent TIAL1 target transcripts, indicating an important role of TIAL1 in cholesterol synthesis and secretion. The functional relevance of these targets was confirmed by showing that TIAL1 influences their translation in hepatocytes. Mutant Tial1 mice exhibit altered cholesterol synthesis, APOB secretion and plasma cholesterol levels. Our results demonstrate that viP-CLIP can identify physiologically relevant RBP targets by finding a factor implicated in the negative feedback regulation of cholesterol biosynthesis. - Heat-inactivated modified vaccinia virus Ankara boosts Th1 cellular and humoral immunity as a vaccine adjuvant
Ning Yang, Aitor Garcia, Cindy Meyer, Thomas Tuschl, Taha Merghoub, Jedd D. Wolchok, Liang Deng
Npj Vaccines, 2022
Protein or peptide-based subunit vaccines have generated excitement and renewed interest in combating human cancer or COVID-19 outbreak. One major concern for subunit vaccine application is the weak immune responses induced by protein or peptides. Developing novel and effective vaccine adjuvants are critical for the success of subunit vaccines. Here we explored the potential of heat-inactivated MVA (heat-iMVA) as a vaccine adjuvant. Heat-iMVA dramatically enhances T cell responses and antibodies responses, mainly toward Th1 immune responses when combined with protein or peptide-based immunogen. The adjuvant effect of Heat-iMVA is stronger than live MVA and is dependent on the cGAS/STING-mediated cytosolic DNA-sensing pathway. In a therapeutic vaccination model based on tumor neoantigen peptide vaccine, Heat-iMVA significantly extended the survival and delayed tumor growth. When combined with SARS-CoV-2 spike protein, Heat-iMVA induced more robust spike-specific antibody production and more potent neutralization antibodies. Our results support that Heat-iMVA can be developed as a safe and potent vaccine adjuvant for subunit vaccines against cancer or SARS-CoV-2. - Publisher Correction: Expanding the binding specificity for RNA recognition by a PUF domain (Nature Communications, (2021), 12, 1, (5107), 10.1038/s41467-021-25433-6)
Wei Zhou, Daniel Melamed, Gabor Banyai, Cindy Meyer, Thomas Tuschl, Marvin Wickens, Junyue Cao, Stanley Fields
Nature Communications, 2022 - Combination of antiviral drugs inhibits SARS-CoV-2 polymerase and exonuclease and demonstrates COVID-19 therapeutic potential in viral cell culture
Xuanting Wang, Carolina Q. Sacramento, Steffen Jockusch, Otávio Augusto Chaves, Chuanjuan Tao, Natalia Fintelman-Rodrigues, Minchen Chien, Jairo R. Temerozo, Xiaoxu Li, Shiv Kumar, Wei Xie, Dinshaw J. Patel, Cindy Meyer, Aitor Garzia, Thomas Tuschl, Patrícia T. Bozza, James J. Russo, Thiago Moreno L. Souza, Jingyue Ju
Communications Biology, 2022
SARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. Combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease could overcome this deficiency. Here we report the identification of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir as SARS-CoV-2 exonuclease inhibitors. In the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision. Due to its unique structure, Tenofovir-terminated RNA was highly resistant to exonuclease excision even in the absence of Pibrentasvir. Viral cell culture studies also demonstrate significant synergy using this combination strategy. This study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment. - Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells
Xammy Nguyenla, Eddie Wehri, Erik Van Dis, Scott B. Biering, Livia H. Yamashiro, Chi Zhu, Julien Stroumza, Claire Dugast-Darzacq, Thomas G. W. Graham, Xuanting Wang, Steffen Jockusch, Chuanjuan Tao, Minchen Chien, Wei Xie, Dinshaw J. Patel, Cindy Meyer, Aitor Garzia, Thomas Tuschl, James J. Russo, Jingyue Ju, Anders M. Näär, Sarah Stanley, Julia Schaletzky
Scientific Reports, 2022
SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir’s apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir. - Expanding the binding specificity for RNA recognition by a PUF domain
Wei Zhou, Daniel Melamed, Gabor Banyai, Cindy Meyer, Thomas Tuschl, Marvin Wickens, Junyue Cao, Stanley Fields
Nature Communications, 2021
The ability to design a protein to bind specifically to a target RNA enables numerous applications, with the modular architecture of the PUF domain lending itself to new RNA-binding specificities. For each repeat of the Pumilio-1 PUF domain, we generate a library that contains the 8,000 possible combinations of amino acid substitutions at residues critical for RNA contact. We carry out yeast three-hybrid selections with each library against the RNA recognition sequence for Pumilio-1, with any possible base present at the position recognized by the randomized repeat. We use sequencing to score the binding of each variant, identifying many variants with highly repeat-specific interactions. From these data, we generate an RNA binding code specific to each repeat and base. We use this code to design PUF domains against 16 RNAs, and find that some of these domains recognize RNAs with two, three or four changes from the wild type sequence. - The E3 ubiquitin ligase RNF10 modifies 40S ribosomal subunits of ribosomes compromised in translation
Aitor Garzia, Cindy Meyer, Thomas Tuschl
Cell Reports, 2021
Reversible monoubiquitination of small subunit ribosomal proteins RPS2/uS5 and RPS3/uS3 has been noted to occur on ribosomes involved in ZNF598-dependent mRNA surveillance. Subsequent deubiquitination of RPS2 and RPS3 by USP10 is critical for recycling of stalled ribosomes in a process known as ribosome-associated quality control. Here, we identify and characterize the RPS2- and RPS3-specific E3 ligase Really Interesting New Gene (RING) finger protein 10 (RNF10) and its role in translation. Overexpression of RNF10 increases 40S ribosomal subunit degradation similarly to the knockout of USP10. Although a substantial fraction of RNF10-mediated RPS2 and RPS3 monoubiquitination results from ZNF598-dependent sensing of collided ribosomes, ZNF598-independent impairment of translation initiation and elongation also contributes to RPS2 and RPS3 monoubiquitination. RNF10 photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) identifies crosslinked mRNAs, tRNAs, and 18S rRNAs, indicating recruitment of RNF10 to ribosomes stalled in translation. These impeded ribosomes are tagged by ubiquitin at their 40S subunit for subsequent programmed degradation unless rescued by USP10. - The G3BP1-Family-USP10 Deubiquitinase Complex Rescues Ubiquitinated 40S Subunits of Ribosomes Stalled in Translation from Lysosomal Degradation
Cindy Meyer, Aitor Garzia, Pavel Morozov, Henrik Molina, Thomas Tuschl
Molecular Cell, 2020 - The RNA-Binding Protein A1CF Regulates Hepatic Fructose and Glycerol Metabolism via Alternative RNA Splicing
Kostas C. Nikolaou, Hasan Vatandaslar, Cindy Meyer, Marc W. Schmid, Thomas Tuschl, Markus Stoffel
Cell Reports, 2019 - The Extracellular RNA Communication Consortium: Establishing Foundational Knowledge and Technologies for Extracellular RNA Research
Saumya Das, K. Mark Ansel, Markus Bitzer, Xandra O. Breakefield, Alain Charest, David J. Galas, Mark B. Gerstein, Mihir Gupta, Aleksandar Milosavljevic, Michael T. McManus, Tushar Patel, Robert L. Raffai, Joel Rozowsky, Matthew E. Roth, Julie A. Saugstad, Kendall Van Keuren-Jensen, Alissa M. Weaver, Louise C. Laurent, Asim B. Abdel-Mageed, Catherine Adamidi, P. David Adelson, Kemal M. Akat, Eric Alsop, K. Mark Ansel, Jorge Arango, Neil Aronin, Seda Kilinc Avsaroglu, Azadeh Azizian, Leonora Balaj, Iddo Z. Ben-Dov, Karl Bertram, Markus Bitzer, Robert Blelloch, Kimberly A. Bogardus, Xandra Owens Breakefield, George A. Calin, Bob S. Carter, Al Charest, Clark C. Chen, Tanuja Chitnis, Robert J. Coffey, Amanda Courtright-Lim, Saumya Das, Amrita Datta, Peter DeHoff, Thomas G. Diacovo, David J. Erle, Alton Etheridge, Marc Ferrer, Jeffrey L. Franklin, Jane E. Freedman, David J. Galas, Timur Galeev, Roopali Gandhi, Aitor Garcia, Mark Bender Gerstein, Vikas Ghai, Ionita Calin Ghiran, Maria D. Giraldez, Andrei Goga, Tasos Gogakos, Beatrice Goilav, Stephen J. Gould, Peixuan Guo, Mihir Gupta, Fred Hochberg, Bo Huang, Matt Huentelman, Craig Hunter, Elizabeth Hutchins, Andrew R. Jackson, M. Yashar S. Kalani, Pinar Kanlikilicer, Reka Agnes Karaszti, Kendall Van Keuren-Jensen, Anastasia Khvorova, Yong Kim, Hogyoung Kim, Taek Kyun Kim, Robert Kitchen, Richard P. Kraig, Anna M. Krichevsky, Raymond Y. Kwong, Louise C. Laurent, Minyoung Lee, Noelle L’Etoile, Shawn E. Levy, Feng Li, Jenny Li, Xin Li, Gabriel Lopez-Berestein, Rocco Lucero, Bogdan Mateescu, A.C. Matin, Klaas E.A. Max, Michael T. McManus, Thorsten R. Mempel, Cindy Meyer, Aleksandar Milosavljevic, Debasis Mondal, Kenneth Jay Mukamal, Oscar D. Murillo, Thangamani Muthukumar, Deborah A. Nickerson, Christopher J. O’Donnell, Dinshaw J. Patel, Tushar Patel, James G. Patton, Anu Paul, Elaine R. Peskind, Mitch A. Phelps, Chaim Putterman, Peter J. Quesenberry, Joseph F. Quinn, Robert L. Raffai, Saritha Ranabothu, Shannon Jiang Rao, Cristian Rodriguez-Aguayo, Anthony Rosenzweig, Matthew E. Roth, Joel Rozowsky, Marc S. Sabatine, Nikita A. Sakhanenko, Julie Anne Saugstad, Thomas D. Schmittgen, Neethu Shah, Ravi Shah, Kerby Shedden, Jian Shi, Anil K. Sood, Anuoluwapo Sopeyin, Ryan M. Spengler, Robert Spetzler, Srimeenakshi Srinivasan, Sai Lakshmi Subramanian, Manikkam Suthanthiran, Kahraman Tanriverdi, Yun Teng, Muneesh Tewari, William Thistlethwaite, Thomas Tuschl, Karolina Kaczor Urbanowicz, Kasey C. Vickers, Olivier Voinnet, Kai Wang, Alissa M. Weaver, Zhiyun Wei, Howard L. Weiner, Zachary R. Weiss, Zev Williams, David T.W. Wong, Prescott G. Woodruff, Xinshu Xiao, Irene K. Yan, Ashish Yeri, Bing Zhang, Huang-Ge Zhang
Cell, 2019 - The TIA1 RNA-Binding Protein Family Regulates EIF2AK2-Mediated Stress Response and Cell Cycle Progression
Cindy Meyer, Aitor Garzia, Michael Mazzola, Stefanie Gerstberger, Henrik Molina, Thomas Tuschl
Molecular Cell, 2018 - PAR-CLIP for discovering target sites of RNA-binding proteins
Aitor Garzia, Pavel Morozov, Marcin Sajek, Cindy Meyer, Thomas Tuschl
Methods in Molecular Biology, 2018 - The Conserved RNA Exonuclease Rexo5 Is Required for 3′ End Maturation of 28S rRNA, 5S rRNA, and snoRNAs
Stefanie Gerstberger, Cindy Meyer, Sigi Benjamin-Hong, Joe Rodriguez, Daniel Briskin, Claudia Bognanni, Kimberly Bogardus, Hermann Steller, Thomas Tuschl
Cell Reports, 2017 - Characterizing Expression and Processing of Precursor and Mature Human tRNAs by Hydro-tRNAseq and PAR-CLIP
Tasos Gogakos, Miguel Brown, Aitor Garzia, Cindy Meyer, Markus Hafner, Thomas Tuschl
Cell Reports, 2017 - The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs
Aitor Garzia, Seyed Mehdi Jafarnejad, Cindy Meyer, Clément Chapat, Tasos Gogakos, Pavel Morozov, Mehdi Amiri, Maayan Shapiro, Henrik Molina, Thomas Tuschl, Nahum Sonenberg
Nature Communications, 2017 - Simultaneous detection of the subcellular localization of RNAs and proteins in cultured cells by combined multicolor RNA-FISH and IF
Cindy Meyer, Aitor Garzia, Thomas Tuschl
Methods, 2017 - Optimization of PAR-CLIP for transcriptome-wide identification of binding sites of RNA-binding proteins
Aitor Garzia, Cindy Meyer, Pavel Morozov, Marcin Sajek, Thomas Tuschl
Methods, 2017 - DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs
Masashi Yamaji, Miki Jishage, Cindy Meyer, Hemant Suryawanshi, Evan Der, Misaki Yamaji, Aitor Garzia, Pavel Morozov, Sudhir Manickavel, Hannah L. McFarland, Robert G. Roeder, Markus Hafner, Thomas Tuschl
Nature, 2017 - RAID3 - An interleukin-6 receptor-binding aptamer with post-selective modification-resistant affinity
Florian Mittelberger, Cindy Meyer, Georg H Waetzig, Martin Zacharias, Erica Valentini, Dmitri I Svergun, Katharina Berg, Inken Lorenzen, Joachim Grötzinger, Stefan Rose-John, Ulrich Hahn
RNA Biology, 2015 - SDA, a DNA aptamer inhibiting E- And P-Selectin mediated adhesion of cancer and leukemia cells, the first and pivotal step in transendothelial migration during metastasis formation
Rassa Faryammanesh, Tobias Lange, Eileen Magbanua, Sina Haas, Cindy Meyer, Daniel Wicklein, Udo Schumacher, Ulrich Hahn
Plos One, 2014 - Chlorin e6 conjugated interleukin-6 receptor aptamers selectively kill target cells upon irradiation
Sven Kruspe, Cindy Meyer, Ulrich Hahn
Molecular Therapy Nucleic Acids, 2014 - Stabilized interleukin-6 receptor binding RNA aptamers
Cindy Meyer, Katharina Berg, Katja Eydeler-Haeder, Inken Lorenzen, Joachim Grötzinger, Stefan Rose-John, Ulrich Hahn
RNA Biology, 2014 - Identification of the RNA recognition element of the RBPMS family of RNA-binding proteins and their transcriptome-wide mRNA targets
T. A. Farazi, C. S. Leonhardt, N. Mukherjee, A. Mihailovic, S. Li, K. E. A. Max, C. Meyer, M. Yamaji, P. Cekan, N. C. Jacobs, S. Gerstberger, C. Bognanni, E. Larsson, U. Ohler, T. Tuschl
RNA, 2014 - Rna aptamer design
Cindy Meyer, Ulrich Hahn, Andrew E. Torda
De Novo Molecular Design, 2013 - D(GGGT)4 and r(GGGU)4 are both HIV-1 inhibitors and interleukin-6 receptor aptamers
Eileen Magbanua, Tijana Zivkovic, Björn Hansen, Niklas Beschorner, Cindy Meyer, Inken Lorenzen, Joachim Grötzinger, Joachim Hauber, Andrew E. Torda, Günter Mayer, Stefan Rose-John, Ulrich Hahn
RNA Biology, 2013 - Human α 2-macroglobulin-another variation on the Venus flytrap
Cindy Meyer, Winfried Hinrichs, Ulrich Hahn
Angewandte Chemie International Edition, 2012 - Interleukin-6 receptor specific RNA aptamers for cargo delivery into target cells
Cindy Meyer, Katja Eydeler, Eileen Magbanua, Tijana Zivkovic, Nicolas Piganeau, Inken Lorenzen, Joachim Grötzinger, Günter Mayer, Stefan Rose-John, Ulrich Hahn
RNA Biology, 2012 - Cell-specific aptamers as emerging therapeutics
Cindy Meyer, Ulrich Hahn, Andrea Rentmeister
Journal of Nucleic Acids, 2011 - RNA dimerization monitored by fluorescence correlation spectroscopy
Arne Werner, Victor V. Skakun, Cindy Meyer, Ulrich Hahn
European Biophysics Journal, 2011 - Cell-SELEX: Cell-specific aptamers in diagnosis and therapy
Cindy Meyer, Ulrich Hahn, Andrea Rentmeister
Biospektrum, 2011
