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1. A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis

Author

Pooja Gupta, Sherine E. Thomas, Shaymaa A. Zaidan, Maria A. Pasillas, James Cory-Wright, Víctor Sebastián-Pérez, Ailidh Burgess, Emma Cattermole, Clio Meghir, Chris Abell, Anthony G. Coyne, William R. Jacobs, Jr., Tom L. Blundell, Sangeeta Tiwari, and Vítor Mendes

Subjects
ArgB, ArgC, ArgD, ArgF, Mycobacterium tuberculosis, FBDD, Biotechnology, TP248.13-248.65
Abstract

The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes.

Published
2021
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2. A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis

Author

William R. Jacobs, Maria A. Pasillas, Ailidh Burgess, Tom L. Blundell, Sangeeta Tiwari, Anthony G. Coyne, James Cory-Wright, Vitor Mendes, Clio Meghir, Víctor Sebastián-Pérez, Sherine E. Thomas, Shaymaa A. Zaidan, Emma Cattermole, Pooja Gupta, Chris Abell, Bill & Melinda Gates Foundation, Gates Cambridge Scholarships, Wellcome Trust, National Institutes of Health (US), Thomas, Sherine E. [0000-0003-1152-4312], Sebastián-Pérez, Víctor [0000-0002-8248-4496], Burgess, Ailidh [0000-0002-9643-3163], Cattermole, Emma [0000-0002-0671-2207], Meghir, Clio [0000-0002-1551-6726], Abell, Chris [0000-0001-9174-1987], Coyne, Anthony G. [0000-0003-0205-5630], Jacobs Jr, William R. [0000-0003-3321-3080], Mendes, Vítor [0000-0002-2734-2444], Thomas, Sherine E., Sebastián-Pérez, Víctor, Burgess, Ailidh, Cattermole, Emma, Meghir, Clio, Abell, Chris, Coyne, Anthony G., Jacobs Jr, William R., Mendes, Vítor, Thomas, Sherine [0000-0003-1152-4312], Coyne, Anthony [0000-0003-0205-5630], Blundell, Tom [0000-0002-2708-8992], and Apollo - University of Cambridge Repository

Subjects
NMR, Nuclear magnetic resonance, Tuberculosis, Arginine, TB, tuberculosis, Auxotrophy, Biophysics, Crystallographic data, Biology, Biochemistry, Mycobacterium tuberculosis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Biosynthesis, Structural Biology, Genetics, medicine, 030304 developmental biology, ComputingMethodologies_COMPUTERGRAPHICS, ASU, asymmetric unit, chemistry.chemical_classification, 0303 health sciences, Drug discovery, ArgB, ArgD, ArgC, ArgF, medicine.disease, biology.organism_classification, Computer Science Applications, FBDD, Fragment-based drug discovery, Enzyme, chemistry, DSF, Differential scanning fluorimetry, 030220 oncology & carcinogenesis, FBDD, ITC, Isothermal titration calorimetry, TP248.13-248.65, Research Article, SPR, Surface plasmon resonance, Biotechnology
Abstract

16 p.-8 fig.-4 tab., The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes., This work was funded by Bill and Melinda Gates Foundation HIT-TB (OPP1024021) and SHORTEN-TB (OPP1158806). PG was funded by a Gates Cambridge Scholarship. TLB is funded by the Wellcome Trust (Wellcome Trust Investigator Award 200814_Z_16_Z: RG83114). ST acknowledges SC1GM140968 grant from National Institute of Health to support this work.

Published
2021

3. A COVID moonshot: assessment of ligand binding to the SARS-CoV-2 main protease by saturation transfer difference NMR spectroscopy

Author

Georgios A. Spyroulias, Minos-Timotheos Matsoukas, Anastassia L. Kantsadi, Ioannis Vakonakis, and Emma Cattermole

Subjects
0301 basic medicine, 030103 biophysics, Antagonists & inhibitors, Coronavirus disease 2019 (COVID-19), medicine.medical_treatment, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Context (language use), Computational biology, Molecular dynamics, Biochemistry, 01 natural sciences, Article, 03 medical and health sciences, medicine, Humans, Protease Inhibitors, Coronavirus 3C Proteases, Spectroscopy, 030304 developmental biology, 0303 health sciences, Protease, SARS-CoV-2, 010405 organic chemistry, Chemistry, COVID-19, Nuclear magnetic resonance spectroscopy, Ligand (biochemistry), NMR, COVID-19 Drug Treatment, 3. Good health, 0104 chemical sciences, 030104 developmental biology, Viral replication, Saturation transfer, STD, Mpro
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of the coronavirus disease 2019, for which no effective antiviral therapeutics are available. The SARS-CoV-2 main protease (Mpro) is essential for viral replication and constitutes a promising therapeutic target. Many efforts aimed at deriving effective Mpro inhibitors are currently underway, including an international open-science discovery project, codenamed COVID Moonshot. As part of COVID Moonshot, we used saturation transfer difference nuclear magnetic resonance (STD-NMR) spectroscopy to assess the binding of putative Mpro ligands to the viral protease, including molecules identified by crystallographic fragment screening and novel compounds designed as Mpro inhibitors. In this manner, we aimed to complement enzymatic activity assays of Mpro performed by other groups with information on ligand affinity. We have made the Mpro STD-NMR data publicly available. Here, we provide detailed information on the NMR protocols used and challenges faced, thereby placing these data into context. Our goal is to assist the interpretation of Mpro STD-NMR data, thereby accelerating ongoing drug design efforts.

Published
2021

4. A Fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis

Author

Emma Cattermole, Clio Meghir, William R. Jacobs, James Cory-Wright, Víctor Sebastián-Pérez, Sangeeta Tiwari, Tom L. Blundell, Sherine E. Thomas, Pooja Gupta, Ailidh Burgess, Vitor Mendes, Chris Abell, and Anthony G. Coyne

Subjects
Genetics, chemistry.chemical_classification, Tuberculosis, biology, Arginine, Drug discovery, biology.organism_classification, medicine.disease, Mycobacterium tuberculosis, chemistry.chemical_compound, Enzyme, chemistry, Biosynthesis, medicine, Chemical inhibition, Gene
Abstract

The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine, appears to be attractive target for anti-Tuberculosis (TB) drug discovery. Starvation of M. tuberculosis deleted for either argB or argF genes led to rapid sterilization of these strains in mice while Chemical inhibition of ArgJ with Pranlukast was also found to clear chronic M. tuberculosis infection in animal models. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is explored using a fragment-based approach. We reveal several hits for these enzymes validated with biochemical and biophysical assays, and X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential of more enzymes in this pathway to be targeted with dedicated drug discovery programmes.

Published
2021
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5. COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning

Author

Anna Carbery, Annette von Delft, Boris Kovar, Vishwanath Swamy, Ronen Gabizon, Nathan Wright, Charlie Weatherall, Susana Tomasio, Hannah E. Bruce Macdonald, Daniel Zaidmann, Ailsa Powell, P. Gehrtz, Noam Erez, Walter Ward, Vladimir Psenak, Finny S. Varghese, Edward J Griffen, Halina Mikolajek, Sharon Melamed, Emma Cattermole, A. Aimon, Elad Bar-David, Louise Dunnett, Maneesh Pingle, Warren Thompson, Efrat Resnick, William G. Glass, Mark Daniel Calmiano, J. L. Kiappes, Lizbe Koekemoer, Mariana Vaschetto, Andrew Jajack, Nir London, Martin Walsh, Beth MacLean, Charline Giroud, Haim Levy, Anastassia L. Kantsadi, Vladas Oleinikovas, Andrew Thompson, Vincent A. Voelz, Assa Sittner, Tomer Israely, John Spencer, Itai Glinert, Matthew F. D. Hurley, Richard Foster, T.J. Gorrie-Stone, Aarif Shaikh, Gijs J. Overheul, Conor Francis Wild, Michael Fairhead, Benjamin Ian Perry, David Owen, Michelle L. Hill, Peter W. Kenny, Sarma Bvnbs, Galit Cohen, Ralph P. Robinson, Jakir Pinjari, Carina Gileadi, Amir Ben-Shmuel, Shay Weiss, Victor L. Rangel, Matthew C. Robinson, Anthony Tumber, D. Fearon, Jag Paul Heer, Boaz Politi, Nicole Zitzmann, Claire Strain-Damerell, Tika R. Malla, Oleg M. Michurin, Peter K. Eastman, Christopher J. Schofield, Matthew Wittmann, Jin Pan, Eric Jnoff, Shirly Duberstein, Mihaela D. Smilova, Haim Barr, Ronald P. van Rij, Joseph E. Coffland, Garrett M. Morris, Austin Clyde, Khriesto A. Shurrush, Einat B. Vitner, Ruby Pai, Alessandro Contini, St Patrick Reid, Jose Brandao Neto, Lisa Cox, Tatiana Matviiuk, Jiye Shi, Sam Horrell, Ioannis Vakonakis, Aaron Morris, Hadeer Zidane, Juliane Brun, Yfat Yahalom-Ronen, Hadas Tamir, R. Skyner, Tobias John, John D. Chodera, Nir Paran, Alex Dias, Dominic Rufa, Willam McCorkindale, Reut Puni, Hagit Achdout, Rachael Tennant, Holly Foster, Tim Dudgeon, Bruce A. Lefker, Rambabu N. Reddi, Marian V. Gorichko, Frank von Delft, Alpha A. Lee, Milan Cvitkovic, T. Krojer, Demetri Moustakas, Oleg Fedorov, Robert C. Glen, Jason C. Cole, Petra Lukacik, Matteo P. Ferla, Melissa L Bobby, Adam Smalley, Jim Bennett, Melody Jane Morwitzer, and Alice Douangamath

Subjects
Open science, Protease, Computer science, business.industry, Drug discovery, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, Crowdsourcing, Machine learning, computer.software_genre, Enzymatic Assays, medicine, Ic50 values, Artificial intelligence, business, Throughput (business), computer
Abstract

Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.

Published
2020
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6. Open Science Discovery of Potent Non-Covalent SARS-CoV-2 Main Protease Inhibitors

Author

von Delft F, Ronen Gabizon, Wild Cf, Anastassia L. Kantsadi, Peter W. Kenny, Koekemoer L, Matteo P. Ferla, Noam Erez, Sharon Melamed, Adam Smalley, Gijs J. Overheul, Jag Paul Heer, Shaikh A, Tika R. Malla, R.S. Fernandes, Christopher J. Schofield, Moustakas D, Pai R, MacLean B, T. Krojer, Finny S. Varghese, Elad Bar-David, Hagit Achdout, Gregory R. Bowman, Lefker Ba, Kovar B, Charlie Weatherall, Tennant R, Griffen Ej, Yfat Yahalom-Ronen, Louise Dunnett, Emma Cattermole, Bvnbs S, Chernyshenko E, Ripka Eg, Kim Donckers, Efrat Resnick, Nir Paran, J. L. Kiappes, Einat B. Vitner, Dotson Dl, Mark Daniel Calmiano, Juliane Brun, Victor L. Rangel, Matthew F. D. Hurley, Richard Foster, Garrett M. Morris, Vaschetto M, Austin Clyde, Shay Weiss, Pan J, Nir London, William McCorkindale, Dudgeon T, Martin A. Walsh, Borden B, Haim Barr, John Spencer, Zaidmann D, Alice Douangamath, Robinson Rp, Alexandre Dias, John D. Chodera, Morris A, Marian V. Gorichko, Oleg Fedorov, V.O. Gawriljuk, Petra Lukacik, Puni R, Pinjari J, Shafeev M, Dirk Jochmans, Assa Sittner, T.J. Gorrie-Stone, White Km, Amir Ben-Shmuel, Ioannis Vakonakis, Boaz Politi, Rambabu N. Reddi, Joseph E. Coffland, Itai Glinert, Matthew C. Robinson, Ferrins L, Tomasio S, Alpha A. Lee, Khriesto A. Shurrush, Holly Foster, A. Aimon, Boby Ml, Andrea Volkamer, Alessandro Contini, Voelz, Tobias John, Galit Cohen, A.M. Nakamura, Horrell S, G.D. Noske, Jim Bennett, Oleg M. Michurin, Nicholas A. Wright, Smilova, von Delft A, Ward W, Haim Levy, Tomer Israely, Fate G, McGovern Bl, Anna Carbery, David R. Owen, Zidane H, Cox L, Michael Fairhead, Psenak, Carina Gileadi, Wittmann M, Morwitzer Mj, Solmesky Lj, Anthony Tumber, Robert C. Glen, Eric Jnoff, Reid Sp, Sukrit Singh, Steven De Jonghe, Claire Strain-Damerell, Jason C. Cole, A.J. Powell, Rosales R, Nicole Zitzmann, D. Fearon, Nguyen L, Rodriguez-Guerra J, Shirly Duberstein, Andrew Thompson, Johan Neyts, Benjamin Ian Perry, van Rij Rp, Jose Brandao Neto, William G. Glass, Rufa D, Charline Giroud, Peter Eastman, Hannah E. Bruce Macdonald, Glaucius Oliva, Mark A. Hill, Laura Vangeel, Jiye Shi, Hadas Tamir, R. Skyner, Mikolajek H, Adolfo García-Sastre, Oleinikovas, Pingle M, Henry M, Cvitkovic M, Milne Bf, Hart Sh, Eyermann Cj, Thompson W, Matviiuk T, Andre S. Godoy, Swamy, P. Gehrtz, and Jajack A

Subjects
Open science, Open knowledge, Protease, Structural biology, Drug discovery, Computer science, Non covalent, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, medicine, Protease inhibitor (pharmacology), Computational biology
Abstract

The COVID-19 pandemic was a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Pandemics could be prevented in principle by accessible, easily deployable broad-spectrum oral antivirals. Here we report the results of theCOVID Moonshot, a fully open-science, crowd sourced, structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical series that is differentiated from current Mpro inhibitors in that it maintains a new non-covalent, non-peptidic scaffold with nanomolar potency. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations and high-throughput chemistry. In the process, we generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>840 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.

Published
2020
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7. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Author

Jitske Jansen, Katharina C. Reimer, James S. Nagai, Finny S. Varghese, Gijs J. Overheul, Marit de Beer, Rona Roverts, Deniz Daviran, Liline A.S. Fermin, Brigith Willemsen, Marcel Beukenboom, Sonja Djudjaj, Saskia von Stillfried, Larissa E. van Eijk, Mirjam Mastik, Marian Bulthuis, Wilfred den Dunnen, Harry van Goor, Jan-Luuk Hillebrands, Sergio H. Triana, Theodore Alexandrov, Marie-Cherelle Timm, Bartholomeus T. van den Berge, Martijn van den Broek, Quincy Nlandu, Joelle Heijnert, Eric M.J. Bindels, Remco M. Hoogenboezem, Fieke Mooren, Christoph Kuppe, Pascal Miesen, Katrien Grünberg, Ties Ijzermans, Eric J. Steenbergen, Jan Czogalla, Michiel F. Schreuder, Nico Sommerdijk, Anat Akiva, Peter Boor, Victor G. Puelles, Jürgen Floege, Tobias B. Huber, Ronald P. van Rij, Ivan G. Costa, Rebekka K. Schneider, Bart Smeets, Rafael Kramann, Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Melissa L. Boby, Bruce Borden, Gregory R. Bowman, Juliane Brun, Sarma BVNBS, Mark Calmiano, Anna Carbery, Emma Cattermole, Eugene Chernychenko, John D. Choder, Austin Clyde, Joseph E. Coffland, Galit Cohen, Jason Cole, Alessandro Contini, Lisa Cox, Milan Cvitkovic, Alex Dias, Kim Donckers, David L. Dotson, Alica Douangamath, Shirly Duberstein, Tim Dudgeon, Louise Dunnett, Peter K. Eastman, Noam Erez, Charles J. Eyermann, Mike Fairhead, Gwen Fate, Daren Fearon, Oleg Federov, Matteo Ferla, Rafaela S. Fernandes, Lori Ferrins, Richard Foster, Holly Foster, Ronen Gabizon, Adolfo Garcia-Sastre, Victor O. Gawriljuk, Paul Gehrtz, Carina Gileadi, Charline Giroud, William G. Glass, Robert Glen, null Itai glinert, Andre S. Godoy, Marian Gorichko, Tyler Gorrie-Stone, Ed J. Griffen, Storm Hassell Hart, Jag Heer, Micheal Henry, Michelle Hill, Sam Horrell, Matthew F.D. Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Dirk Jochmans, Tobias John, Steven De Jonghe, Anastassia L. Kantsadi, Peter W. Kenny, J.L. Kiappes, Lizbe Koekemoer, Boris Kovar, Tobias Krojer, Alpha A. Lee, Bruce A. Lefker, Haim Levy, Nir London, Petra Lukacik, Hannah Bruce Macdonald, Beth Maclean, Tika R. Malla, Tatiana Matviiuk, Willam McCorkindale, Briana L. McGovern, Sharon Melamed, Oleg Michurin, Halina Mikolajek, Bruce F. Milne, Aaron Morris, Garret M. Morris, Melody Jane Morwitzer, Demetri Moustakas, Aline M. Nakamura, Jose Brandao Neto, Johan Neyts, Luong Nguyen, Gabriela D. Noske, Vladas Oleinikovas, Glaucius Oliva, David Owen, Vladimir Psenak, Ruby Pai, Jin Pan, Nir Paran, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, Ailsa Powell, Reut Puni, Victor L. Rangel, Ranbabu N. Reddi, St Patrick Reid, Efrat Resnick, Emily Grace Ripka, Matthew C. Robinson, Ralph P. Robinson, Jaime Rodriguez-Guerra, Romel Rosales, Dominic Rufa, Chris Schofield, Mikhail Shafeev, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Sukrit Sing, Assa Sittner, Rachael Skyner, Adam Smalley, Mihaela D. Smilova, Leonardo J. Solmesky, John Spencer, Claire Strain-Damarell, Vishwanath Swamy, Hadas Tamir, Rachael Tennant, Warren Thompson, Andrew Thompson, Susana Tomasia, Anthony Tumber, Ioannis Vakonakis, Laura van Geel, Mariana Vaschetto, Einat B. Vitner, Vincent Voelz, Andra Volkamer, Frank von Delft, Annette von Delft, Martin Walsh, Walter Ward, Charlie Weatherall, Shay Weiss, Kris M. White, Conor Francis Wild, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Daniel Zaidmann, Hadeer Zidane, Nicole Zitzmann, Hematology, Developmental Biology, Internal Medicine, Molecular Neuroscience and Ageing Research (MOLAR), Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)

Subjects
FÍGADO, viruses, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Kidney, All institutes and research themes of the Radboud University Medical Center, Post-Acute COVID-19 Syndrome, SDG 3 - Good Health and Well-being, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Genetics, Humans, SARS-CoV-2, human iPSC kidney organoids, fibrosis, fungi, COVID-19, Cell Biology, Clinical and Translational Report, Fibrosis, Organoids, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], kidney injury, Molecular Medicine, protease blocker, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], chronic kidney disease
Abstract

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human induced pluripotent stem cell-derived kidney organoids with SARS-CoV-2. Single cell RNA-sequencing indicated injury and dedifferentiation of infected cells with activation of pro-fibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in Long-COVID., Graphical Abstract, Jansen, Reimer, Nagai et al report that SARS-CoV-2 infects kidney cells and is associated with kidney fibrosis in patients. Using single cell transcriptomics of infected kidney organoids, they show that SARS-CoV-2 causes kidney injury and stimulates pro-fibrotic signaling. Viral infection in organoids was inhibited by a recently developed protease blocker.

Published
2022

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