The QCRG AViDD Program

The QCRG (Quantitative Biosciences Institute Coronavirus Research Group) AViDD Program is an interdisciplinary program that aims to identify new direct-acting antivirals for SARS-CoV-2 and 19 other viruses. The project brings together a team of 45 investigators from 14 different institutions in this proposal with a history of collaboration; 31 of these have co-published together on 41 papers on SARS-CoV-2, efforts that have laid a strong foundation for the QCRG AViDD Program.

Initially, the QCRG will focus on eight target classes from eight viral families (Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae, Hantaviridae, Arenaviridae, Nairoviridae and Paramyxoviridae), including seven coronaviruses, with a focus on SARS-CoV-2, where the viral RNA and 12 proteins will be targeted. In addition to the SARS-CoV-2 RNA (Project 1), these will include the Nsp3 PLP and Nsp5 Mpro proteases (Project 2); the Nsp3 macrodomain  (Project 5);  the RdRp polymerase, Nsp7, Nsp8 and Nsp12 (Project 2) the structural proteins E (Project 3), N (Project 6) and M (Projects 3 and 6); the methyltransferases Nsp10/14 and Nsp16 (Project 4); and the accessory protein involved in regulating immune response, Orf9b (Project 6). Although we will focus on SARS-CoV-2, related proteins from 19 other viruses will also be targeted. Using the QCRG Drug Discovery Platform, we will perform screens on these targets, involving fragment campaigns, virtual library docking, and high-throughput screens, to discover inhibitors. These inhibitors will be optimized using cycles of design, structure determination, and testing. In vitro and in vivo pharmacokinetics as well as activity in cellular and mouse models of infection will be carried out, followed by studies involving oral bioavailability, clearance, permeability, solubility, metabolic liabilities, toxicity and efficacy. The final goal of each Project is an Optimized Lead ready for clinical development at Roche. 

Throughout, we will exploit an integrated suite of experimental and computational technologies provided by eight Cores. The Biochemistry Core will provide purified material for the Screening Core, while the structures of  targets and compounds will be determined  through the Cryo-EM, Cryo-ET and crystallography capabilities of the Structural Biology Core. State-of-the-art mass spectrometry in the Proteomics Core will provide mechanistic insight into drug-protein relationships. The Medicinal Chemistry Core will optimize potent on-target compounds and work closely with the In Vitro Virology Core and In Vivo Virology Core to measure and optimize antiviral activity. The Integrative Modeling Core will provide computational support to structure determination and inhibitor discovery throughout the QCRG Drug Discovery Platform. The Administrative Core will help to foster a collaborative environment and will manage the Mentored Project Awards and the Developmental Research Project program, which will bring in new investigators.
 The QCRG AViDD Program will discover and develop inhibitors targeting key viral proteins. Innovation comes from using cutting-edge techniques individually and in combination with each other as well as from the viral proteins and processes targeted (e.g., viral enzymes that act to suppress host immune response). Impact comes from the development of clinical candidates with potent in vivo activity and from the development of a readily shared platform of technologies and target strategies for also treating future pandemics.

There will be an event on Monday, January 24th to discuss the ongoing progress related to the AViDD grant.


Nevan Krogan, QBI UCSF (Lead PI of the Administrative Core and Proteomics Core) is the director of QBI and a leader in connecting systems approaches with mechanistic insight to unravel basic biology of pathogens, such as SARS-CoV-2, HIV, zika, Ebola and dengue. He has led numerous large, collaborative center grants from NIH on a variety of different diseases, from HIV to cancer, and spearheaded the QCRG in early 2020, recruiting scientists from all over the world to study and combat COVID19.

Robert Stroud, QBI UCSF (Lead PI of the Protein Biochemistry Core and Structural Biology Core) is a world-recognized crystallographer with major contributions to structure-based drug design, the study of membrane proteins and HIV integrase and viral proteases.

Michelle Arkin, QBI UCSF (Lead PI of the Screening Core) is widely known for innovations in high-throughput screening (HTS) and fragment discovery and for 14 years has co-run the UCSF Small Molecule Discovery Center with Adam Renslo.

Adam Renslo, QBI UCSF (Lead PI of the Medicinal Chemistry Core) has a Pharma med chem background and deep experience in hit-to-lead and lead optimization, with a longstanding interest in antimicrobial chemotherapy.

David Agard, QBI UCSF (Lead PI of the Structural Biology Core) is a leader in developing Cryo-EM techniques and their applications.

Andrej Sali, QBI UCSF (Lead PI of the Integrative Modeling Core) is a world expert on integrative modeling of protein machines and developed widely used software, such as IMP and MODELLER.

Melanie Ott, Gladstone Institutes/QBI UCSF (Lead PI of the In Vitro Virology Core and In Vivo Virology Core) is the director of the Gladstone Institute of Virology and recognized for her contributions to HIV Cure research and the pathogenesis of hepatitis C virus, zika virus and SARS-CoV-2 infections.

Adolfo Garcia-Sastre, Icahn School of Medicine at Mount Sinai, New York (Lead PI of the In Vivo Virology Core and In Vitro Virology Core) is the director of one of five NIAID-funded Centers of Excellence for Influenza Research and Surveillance and an expert on the molecular biology of negative-strand RNA viruses.

Danielle Swaney, QBI UCSF (Lead PI of the Proteomics Core) is a junior faculty at UCSF, an expert in mass spectrometry and Director of the Thermo Fisher Scientific Proteomics Facility for Disease Target Discovery located at UCSF/Gladstone.

Kevan Shokat, QBI UCSF (Lead PI of Project 1 and Project 4) is among the world’s foremost chemical biologists and has had an outsize impact on drug discovery for difficult targets.

Charles Craik, QBI UCSF (Lead PI of Project 2) is a world leader in protease structure-function, with a longstanding interest in antivirals.

William DeGrado, QBI UCSF (Lead PI of Project 3) is an expert in peptide chemistry, protein design, and drug discovery.

Danica Fujimori, QBI UCSF (Lead PI of Project 4) has deep experience in methyltransferases and demethylases.

James Fraser, QBI UCSF (Lead PI of Project 5 and Project 6) studies macromolecular structure and dynamics and created multi-temperature X-ray data collection approaches for ligand discovery campaigns.


Brian Shoichet, QBI UCSF (Co-I of Project 2, Project 4, Project 5, the Screening Core, and Medicinal Chemistry Core) is an expert in molecular docking, structure-based inhibitor discovery and artifact detection in early discovery.

Jennifer Doudna, UC Berkeley, Gladstone Institutes, QBI UCSF (Co-I of Project 1 and the In Vitro Virology Core) is a Nobel laureate renowned for the discovery of CRISPR and RNA-protein studies.

Eddy Arnold, Rutgers University (Co-I of Project 2) is an expert in antiviral drug discovery and his crystal structures of HIV-1 RT drove the development of two anti-HIV drugs, etravirine and rilpivirine.

Luis Martinez, University of Texas at San Antonio (Co-I of the In Vitro Virology Core) is recognized for generating recombinant arenaviruses, influenza and zika viruses with plasmid-based reverse genetic approaches. His lab has access to a maximum containment BSL-4 laboratory.

Mathias Götte, University of Alberta, Canada (Co-I of Project 2) is the world leader in characterizing the inhibition mechanisms of remdesivir and molnupiravir and focuses on studying and targeting RNA viral replication, with applications to Ebola, Nipah, Lassa, RSV, and influenza.

Masoud Vedadi, University of Toronto, Canada (Co-I of Project 4) focuses on developing new high throughput biophysical and biochemical characterization and screening methods to discover selective inhibitors of methyltransferases.

Marco Vignuzzi, Institut Pasteur, France (Co-I of the In Vitro Virology Core and In Vivo Virology Core) monitors and predicts the evolution of RNA viruses for developing vaccines and antivirals.

Carla Saleh, Institut Pasteur, France (Co-I of the In Vitro Virology Core and In Vivo Virology Core) aims to understand the molecular and cellular aspects of antiviral immunity in insects.

Yifan Cheng, QBI UCSF (Co-I of the Structural Biology Core) is an electron microscopist who redefined the resolution limits of single-particle Cryo-EM to rival the atomic resolution of X-ray crystallography.

Tanja Kortemme, QBI UCSF (Co-I of the Biochemistry Core and Integrative Modeling Core) combines computer science, physics, chemistry, mathematics, engineering and biology to engineer new bioactive molecules.

Kliment Verba, QBI UCSF (Co-I of Project 6 and the Structural Biology Core) is a QBI Fellow who leverages Cryo-EM and high-throughput X-ray crystallography for drug discovery.

Ana Sesma, Icahn School of Medicine at Mount Sinai, New York (Co-I of the In Vitro Virology Core) was recently ranked in the top 5 female NIH-funded investigators and studies innate immune evasion by coronaviruses, zika, HIV, influenza, chikungunya and dengue using human primary cell systems.

Jian Jin, Icahn School of Medicine at Mount Sinai, New York (Co-I of the Medicinal Chemistry Core) is an internationally recognized medicinal chemist and chemical biologist with over 20 years of experience in small-molecule drug discovery.

Judd Hultquist, Northwestern University (Co-I of Project 2) is an expert in developing high-throughput, quantitative methods to assess genetic perturbations in primary cell models of infection.

Kris White, Icahn School of Medicine at Mount Sinai, New York (Co-I of the In Vivo Virology Core) studies influenza replication for target discovery and works towards generation of a universal influenza vaccine.

Randy Albrecht, Icahn School of Medicine at Mount Sinai, New York (Co-I of the In Vivo Virology Core) studies the replication, pathogenesis, transmission, and adaptation of respiratory viruses to new hosts.

Alan Ashworth, QBI UCSF (Co-I of Project 5) is the President of the UCSF Helen Diller Family Comprehensive Cancer Center and an expert in ADP-ribosylation signaling, advancing the concept of synthetic lethality to the clinic with his work on PARP inhibitors.

Davide Ruggero, QBI UCSF (Co-I of Project 1) made numerous breakthrough discoveries in translational machinery and is, with Kevan Shokat, the scientific founder of eFFECTOR, a company testing the selective translation inhibitor zotatifin in patients with mild-to-moderate COVID19.

Gregory Towers, University College London (Co-I of the In Vitro Virology Core) studies virus-host interactions of HIV and SARS-CoV-2 and their relationship to the innate immune system to develop novel antivirals.

Michael Keiser, QBI UCSF (Co-I of the Integrative Modeling Core) develops new approaches to address core challenges in systems pharmacology, such as elucidation of multitarget small-molecule mechanisms and delineation of pharmacological circuits.

Jason Gestwicki, QBI UCSF (Co-I of the Screening Core) uses a chemical biology strategy that includes the discovery and optimization of new chemical inhibitors.

Pedro Beltrao, Instituto Gulbenkian de Ciencia (Co-I of the Integrative Modeling Core) is currently transitioning to ETH Zurich, studies the evolutionary dynamics and functional importance of post-translational regulatory networks and how they are rewired in the context of infection.

Clare Jolly, University College London (Co-I of the In Vitro Virology Core) uses expertise in molecular virology, cell biology and advanced imaging to understand the cell biology of viral infection.

Ignacia Echeverria Riesco, QBI UCSF (Co-I of the Integrative Modeling Core) has expertise in integrative structural modeling.

Robyn Kaake, QBI UCSF (Co-I of the Proteomics Core) has expertise in proteomics techniques with a focus on crosslinking (XL)-MS.

Lorena Zuliani-Alvarez, QBI UCSF (Co-I of the In Vitro Virology Core and Administrative Core) is a senior scientist and the Project Manager of QBI’s infectious disease portfolio, with expertise in molecular virology.

Ursula Schulze-Gahmen, QBI UCSF (Co-I of Project 2) is an accomplished biochemist and structural biologist with experience in viral protein structures and the regulation of HIV transcription.

Manon Eckhardt, QBI UCSF (Co-I of the Administrative Core) is a molecular systems virologist, and project manager with experience in science outreach and DEI programs.


RNA virus families have great genetic heterogeneity that allows wide tropism and cross-species transmission. This group evolved to maximize the manipulation of the cellular machinery for viral replication and the antagonism or evasion of conserved cellular pathways aiming to restrict viral infection. For successful replication, all RNA viruses must complete five stages. First, key proteins in the viral envelope bind to target cell receptors and fuse with the host cell membrane (1-viral entry). Once in the cell cytosol, viral RNA is translated to make the viral proteins that are involved in the generation of the replication complex (2-RNA translation). Viral replication occurs inside cytoplasmic replication organelles or double membrane vesicles that protect the virus RNA from being detected (3-viral replication). Structural viral proteins are produced and package full-length genomes to complete virion formation (4-viral assembly). Viral particles undergo maturation through the ER-Golgi organelles, leading finally to viral egress from the cells (5-viral release). An exquisite balance between viruses and hosts must be achieved, where a virus must silence innate immune activation to complete its life cycle in the cell. A common strategy is to target essential steps of the viral lifecycle to inhibit viral replication, transmission and pathogenicity. The Projects developed by the QCRG AViDD Program aim to disrupt key processes at different stages that can be used alone or in combinations to suppress viral infection and disease.

Project 1: Targeting Viral RNA Using a Sequence Programmable Small Molecule-Oligonucleotide Conjugate (Lead: Shokat; Co-I: Doudna, Ruggero)

Project 2: Developing Antivirals Targeting Proteases and Polymerases of Coronaviruses, Picornaviruses and Bunyavirales (Lead: Craik; Co-I: Arnold, Götte, Schulze-Gahmen, Hultquist, Shoichet)

Project 3: Targeting Viroporins and Coronavirus M Protein (Lead: DeGrado; Co-I: Stroud, Hong)

Project 4: Development of Novel Antivirals Targeting Viral RNA Methylation (Lead: Fujimori; Co-I: Shokat, Vedadi, Shoichet)

Project 5: Inhibiting Viral Macrodomains Using Structure-Based Design (Lead: Fraser; Co-I: Shoichet, Ashworth)


We aim to advance targets and compounds for antiviral drug discovery. The team has expertise in drug discovery from target identification and characterization to Lead Optimization. Using the QCRG Drug Discovery Platform, each of the six Projects will be supported by eight Cores. Overall, we will follow the traditional, iteractive workflow of drug discovery, but each Project and Core includes innovative facets that reflect the unique specialties of the investigators.
The 5-year program will deliver 3–6 Optimized Lead molecules to
 Roche and potentially other partners for preclinical and clinical 
development. Graduation from each stage of the drug discovery
 process will follow design criteria that align with pharmaceutical
 company standards and will be informed by our Target Product
 Profile for an oral antiviral agent

Biochemistry Core (Lead: Stroud; Co-I: Kortemme, Fraser)

Screening Core (Lead: Arkin; Co-I:Shoichet, Fraser, Gestwicki)

Medicinal Chemistry Core (Lead: Renslo; Co-I: Shoichet, Jin)

Structural Biology Core (Lead: Agard; Co-I: Verba, Cheng, Stroud, Fraser)

Integrative Modeling Core (Lead: Sali; Co-I: Echeverria, Beltrao, Keiser, Kortemme)

In Vitro Virology Core (Lead: Ott; Co-I: Garcia-Sastre, Towers, Jolly, Vignuzzi, Sesma, Saleh, Martinez, Zuliani-Alvarez, Doudna)

In Vivo Virology Core (Lead: Garcia-Sastre; Co-I: White, Albrecht, Vignuzzi, Saleh, Ott)

Proteomics Core (Lead: Swaney; Co-I: Kaake, Krogan)

Administrative Core (Lead: Krogan; Co-I: Zuliani-Alvarez, Eckhardt)

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W. R. Arnold, D. Asarnow and Y. Cheng. Classifying liganded states in heterogeneous single-particle cryo-EM datasets. 2022. Microscopy (Oxford, England); DOI: 10.1093/jmicro/dfab044

A. Escalera, A. S. Gonzalez-Reiche, S. Aslam, I. Mena, R. L. Pearl, M. Laporte, A. Fossati, R. Rathnasinghe, H. Alshammary, A. van de Guchte, M. Bouhaddou, T. Kehrer, L. Zuliani-Alvarez, D. A. Meekins, V. Balaraman, C. McDowell, J. A. Richt, G. Bajic, E. M. Sordillo, N. Krogan, V. Simon, R. A. Albrecht, H. van Bakel, A. Garcia-Sastre, T. Aydillo. SARS-CoV-2 variants of concern have acquired mutations associated with an increased spike cleavage. 2022. Cell Host and Microbe (Accepted)

R. Howell, M. Clarke, A-K. Reuschl, T. Chen, S. Abott-Imboden, M. Singer, D. Lowe, C. Bennett, B. Chain, C. Jolly and J. Fisher. Executable network of SARS-CoV-2-Host interaction predicts drug combination treatments. 2022. Npj Digital Medicine (Accepted)

E.A. Ozer, L.M. Simons, O.M. Adewumi, A.A. Fowotade, E.C. Omoruyi, J.A. Adeniji, T.J. Dean, J. Zayas, P.P. Bhimalli, M.K. Ash, A. Godzik, J.R. Schneider, J.I. Mamede, B.O. Taiwo, J.F. Hultquist and R. Lorenzo-Redondo. Multiple expansions of globally uncommon SARS-CoV-2 lineages in Nigeria. Nature Communications (In Press)

S. Siddiqui, K. Bowman, A. Zhu, S. Fischinger, S. Beger, J. Maron, Y. Bartsch, C. Atyeo, M. Gorman, A. Yanis, J. Hultquist, R. Lorenzo-Redondo, E. Ozer, L. Simons, R. Talj, D. Rankin, L. Chapman, K. Meade, J. Steinhart, S. Mullane, S. Siebert, H. Streeck, P. Sabeti, N. Halasa, E. Musk, D. Barouch, A. Menon, E. Nilles, D. Lauffenburger, and G. Alter. Serological markers of SARS-CoV-2 reinfection. 2022. mBio. (In Press)

J. Varona, P. Landete, J. A. Lopez-Martin, V. Estrada, R. Paredes, P. Guisado-Vasco, L. Fernandez de Orueta, M. Torralba, J. Fortun, R. Vates, J. Barberan, B. Clotet, J. Ancochea, D. Carnevali, N. Cabello, L. Porras, P. Gijon, A. Monereo, D. Abad, S. Zuñiga, I. Sola, J. Rodon, J. Vergara-Alert, N. Izquierdo-Useros, S. Fudio, M. J. Pontes, B. de Rivas, P. Giron de Velasco, A. Nieto, J. Gomez, P. Aviles, R. Lubomirov, A. Belgrano, B. Sopesen, K. White, R. Rosales, S. Yildiz, A.-K. Reuschl, L. Thorne, C. Jolly, G. Towers, L. Zuliani-Alvarez, M. Bouhaddou, K. Obernier, B. McGovern, M. L. Rodriguez, L. Enjuanes, J. M. Fernandez-Sousa, N. J. Krogan, J. M. Jimeno, and A. Garcia-Sastre. Pre-clinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19. 2022. Life Science Alliance. DOI: 10.26508/lsa.202101200