Fundraising net proceeds go to COVID-19 Solidarity Response Fund for WHO

Alpha-Ketoamide Inhibitors of the SARS-CoV-2 Main Protease

Rolf Hilgenfeld, PhD, Professor, Institute of Molecular Medicine, University of Luebeck, Germany

At the forefront of battling coronaviruses since 1998, Dr. Rolf Hilgenfeld is focused on determining the mechanism of alpha-ketoamide inhibitors against the novel coronavirus main protease. He recently shared with Emily Le, conference producer of Therapeutic Pipeline for COVID-19, his current efforts to develop a COVID-19 therapy, which brought him out of retirement from research.

EL: Dr. Hilgenfeld, tell us why you are honing in on developing this class of compounds called alpha-ketoamide inhibitors against the novel coronavirus protease. What hypothesis led you to this path?

RH: We determined the crystal structure of the SARS-CoV-2 main protease by early February 2020 (Zhang et al., 2020a, Science 368, 409-412), and used this structural information to optimize the peptidomimetic alpha-ketoamide inhibitors that we had previously designed for other coronavirus main proteases such as those of SARS-CoV-1, MERS-CoV, HCoV NL63, and the bat-CoVs HKU4 and HKU9 (Zhang et al., 2020b, J. Med. Chem. 63, 4562-4578). Our current lead inhibitor, compound 13b, has an extended half-life and can be administered to mice by subcutaneous injection or by inhalation. Twice-daily inhalation at 20 mg/kg results in good levels of the compound in the lung epithelial lining fluid. Systemic application at 50 mg/kg leads to good compound levels in several organs after 24 hours. Further developments will be discussed during my talk.

EL: Can you please tell us about your background and current role.

RH: I was trained as a chemist and later turned biochemist and structural biologist. After obtaining a PhD in macromolecular crystallography at the Free University of Berlin in 1986, I moved to the pharmaceutical giant Hoechst AG (now Sanofi) in Frankfurt. It was here that I built a macromolecular crystallography lab. After my post-doc at the Biocenter in Basel, Switzerland, I returned to Hoechst in 1988 to help design the long-acting insulin Lantus, which reached annual sales of $7 billion in the years after 2000. I also worked on designing inhibitors for HIV-1 protease. In 1995, I accepted a professorship in Structural Biochemistry at the University of Jena and since 2003, I have been at the University of Luebeck as a Professor of Biochemistry and Director of the Institute of Biochemistry. I officially retired in March this year and currently hold a Senior Professorship at the Institute of Molecular Medicine.

EL: The world has been turned upside-down by the novel coronavirus and scientists have been scrambling to figure out potential treatments. A lot of companies and labs have just started working on COVID-19 this year. However, you have an incredibly unique experience of working on coronaviruses for many years. What triggered your interest in studying the novel coronavirus and when did you start your career as a researcher in this field?

RH: Indeed, I have been working on coronaviruses since 1998 — even before the outbreak of SARS-CoV-1 in 2003. I was always interested in proteases; and having worked on the HIV-1 protease during my time in the pharmaceutical industry, I was wondering why the coronavirus main protease is so much bigger than the retroviral protease. So I decided to determine crystal structures of these enzymes. We first determined the structure of the main protease of Transmissible Gastroenteritis Virus (TGEV), a coronavirus that infects pigs and kills young piglets with a very high fatality rate. Then we turned to Human Coronavirus 229E and determined the three-dimensional structure of its main protease and also designed some inhibitors. This was published during the peak of the SARS-1 outbreak in 2003. Subsequently, we determined the structures of many inhibitor complexes of the SARS-CoV-1 main protease; and also, those of several other components of the coronavirus replication complex, including several domains of non-structural protein 3 (Nsp3), and then Nsp7-8 and Nsp9). 

Since the MERS outbreak of 2012, we intensified our efforts to find useful inhibitors of the coronavirus main protease and started designing and developing alpha-ketoamides. We just had started developing our second generation of this compound class when COVID-19 arrived. Within two weeks after the publication of the genomic sequence of the new virus, we had determined the crystal structure of its main protease, as a free enzyme and as complex with our current alpha-ketoamide lead compound (compound 13b).

EL: What makes your approach different?

RH: Our main technology is structure-based drug design. Many people think that virtual screening and drug repurposing is easier and faster, but this view is not supported by the current successes, at least as long the target is the viral main protease.

EL: What stage are you now at with your candidate?

RH: We just entered testing in small-animal models for COVID-19, i.e., a mouse model and a hamster model. We do these experiments in collaboration with groups in Marburg, Germany, and in Leuven, Belgium.

EL: What is the future of research in coronaviruses? 

RH: The future should be bright if the funding exists. Here is my big worry: funding levels may well decline when the pandemic is over. That is exactly what happened after the SARS-1 outbreak. From about 2006 onwards, it was getting more difficult to obtain sufficient funding.

EL: There are two major types of therapy that people are pursuing for COVID treatment at the moment: either antibody or small molecule. In your opinion, which has more potential? 

RH: Both have their justifications and merits. Of course, an efficacious small-molecule therapy will be much more affordable than an antibody therapy.

EL: What do you personally think — can we expect a successful COVID-19 therapy in the market, say, by the end of this year?

EL: If an existing drug is discovered that has already been approved for another indication, then this could be before the end of the year. But apart from Gilead Science’s remdesivir, which has been proven to have limited efficacy against COVID-19, and, for severe cases, perhaps dexamethasone, nothing much has been discovered so far. This is not good news as the expectations are so high. I believe that successful drugs specifically designed for COVID-19 will not be in the market before 2025 or so.

EL: What talk(s) are you looking forward to the most at this Therapeutic Pipeline for COVID-19 meeting?

RH: I look forward to the whole meeting, I am sure I will be able to learn a lot!

If you would like to hear Dr. Rolf Hilgenfeld live at the Therapeutic Pipeline for COVID-19 Virtual Meeting, register today with a 30% Discount Promo Code: interview30 (Apply before checkout).

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James E. Crowe, Jr., MD,

Director, Vanderbilt Vaccine Center; Professor, Pediatrics and Pathology, Microbiology and Immunology, Ann Scott Carell Chair; Founder, IDBiologics

Dr. Crowe’s laboratory has a broad portfolio of work in the area of viral immunology and antibody sciences, with the goal to discover mechanisms of immunity important to developing new therapeutics and vaccines.

Dr. Crowe received his MD degree from the University of North Carolina at Chapel Hill, where he also completed his pediatrics residency. Following his clinical training, Dr. Crowe received five years of post-doctoral training in the laboratory of Infectious Diseases at the NIH. He completed infectious diseases fellowship training in 1996 at Vanderbilt and has run an independent laboratory at Vanderbilt since that time. He is currently Professor of Pediatrics and of Pathology, Microbiology and Immunology, and the Ann Scott Carell Chair, Vanderbilt University Medical Center. The laboratory’s work has been published in over 300 publications in high-quality science journals including CellScience and Nature, and leading medical journals including the New England Journal of Medicine and JAMA. Dr. Crowe was elected to the National Academy of Medicine in 2014 and the National Academy of Inventors in 2017. He has been the recipient of investigator awards from the March of Dimes, American Society for Microbiology, Pediatric Infectious Diseases Society, and Society for Pediatric Research. He was awarded the Judson Infectious Daland Prize of the American Philosophical Society, the Oswald Avery Award of the IDSA, the E. Mead Johnson Award for Excellence in Pediatrics, the Outstanding Investigator Award of the American Federation for Medical Research, the Norman J. Siegel Award of the American Pediatric Society, the Samuel Rosenthal Prize for Excellence in Academic Pediatrics, the Stanley J. Korsmeyer Award of American Society for Clinical Investigation, the Distinguished Medical Alumnus Award from UNC School of Medicine, Chapel Hill, NC. He is an elected Fellow of AAM, AAAS, ASCI, and AAP, IDSA, APS, and others. His research team was selected as the Best Academic Research Team at the 11th Annual Vaccine Industry Excellence Awards. He was awarded the inaugural 2019 Merck Future Insight Prize, a 1M Euro prize shared with Pardis Sabeti. 

He is the Founder of IDBiologics, Inc., an early-stage biotech company developing human monoclonal antibodies for infectious diseases.

Daniel Chen, MD, PhD

CMO, IGM Bioscience

Daniel S. Chen, MD, PhD, is the Chief Medical Officer for IGM Biosciences, and former Vice President, Global Head of Cancer Immunotherapy Development at Genentech/Roche.  He received a BS degree in Biology from the Massachusetts Institute of Technology (1990), a PhD in Microbiology & Immunology (1996), and MD (1998) from the University of Southern California. His PhD work and publications focused on “Early Events in Coronavirus Infection.”

Daniel completed an Internal Medicine Residency and Medical Oncology Fellowship at Stanford University (2003). He went on to complete a Post-doctoral fellowship with Mark Davis in Immunology, where he was a Howard Hughes Medical Institute Associate. He also ran the metastatic melanoma clinic at the Stanford Cancer Center from 2003-2006. In that time, he studied human anti-cancer immune responses pre- and post-cancer vaccination and cytokine administration to determine why anti-tumor immune responses were not more clinically effective. He received a U19 grant to develop better immunologic tools to interrogate human immune responses and ultimately patented the MHC cellular microarray to detect and functionally characterize antigen-specific T cell states.

He continued as Adjunct Clinical Faculty at Stanford from 2006-2016, where he cared for melanoma patients. At Genentech from 2006-2018, Daniel focused on the clinical development of anti-angiogenic and immune-modulatory targeted therapies in both early and late development, as well as the diagnostic tools to aid their development. This included leading the clinical development for atezolizumab, a PD-L1 inhibitor, from the time the program was in research through IND, Phase I, Phase II, Phase III, to filing and approvals in multiple indications worldwide. At IGM, Daniel focuses on the development of novel engineered multivalent and multispecific therapeutics. He is a reviewer for Nature, Immunity, and Clinical Cancer Research, serves on the Board of Directors for SITC, co-chair of the CRI cancer Immunotherapy consortium, gave the keynote presentation at the AACR NCI EORTC Annual Meeting 2014 and presented at the US Congressional Briefing on Immuno Oncology in 2017. He has continued to publish with academic and industry collaborators in the field of cancer immunotherapy, including the often-referenced Chen and Mellman manuscripts, “Elements of cancer immunity and the cancer-immune set point” and “Oncology meets Immunology: The Cancer-Immunity Cycle.”

Imre Berger

Founding Director, Max Planck Bristol Centre; Chair in Biochemistry and Chemistry; University of Bristol UK

Imre Berger was trained as a biochemist and synthetic biologist at Leibniz University and Medical School (MHH) in Hannover (Germany), at MIT (Cambridge, USA), and at ETH Zurich (Switzerland). Imre’s team develops enabling methods for DNA delivery and genome engineering, engineers synthetic vaccines and nanosensors and researches the structure and mechanism of multiprotein complexes in human health and disease. After Group Leader posts at ETH (2005) and EMBL (2007), Berger joined Bristol as Full Professor of Biochemistry (2014) with a joint appointment in Chemistry (2019). He is Founding Director of the Max Planck Centre for Minimal Biology in Bristol, Director of the BBSRC/EPSRC research center for synthetic biology BrisSynBio and Co-director of the Bristol Biodesign Institute BBI.

Imre Berger holds international patents for DNA and protein technologies, co-founded three biotech companies, and received numerous distinctions, notably the Swiss Technology Award, the W.A. DeVigier Foundation Award, and a Wellcome Trust Senior Investigator Award for his innovative research. Since 2019, he is an Investigator of the European Research Council (ERC).

Prof. Berger has participated in leading roles in numerous European Commission (EC) projects, including the pan-European structural biology infrastructure INSTRUCT. He has been Coordinator of the EC FP7 HEALTH ComplexINC project enhancing production tools for complex biologics in academic and industrial R&D (2011-2016) and is partner in the EPSRC funded Innovative Future Vaccine Manufacturing Research Hub.

Sina Bavari, PhD

CSO, Edge BioInnovation Consulting and Management; former CSO, Scientific Director US Army Medical Research Institute of Infectious Diseases (USAMRIID)

Dr. Sina Bavari is the co-founder of Healion Bio. He is one of the lead (non-gov) scientific adviser to the World Health Organization on SARSCoV-2. He has spent over 30 years developing rapid response diagnostics, prophylaxis, therapeutics, and vaccines for some of the world’s deadliest infectious diseases. Prior to co-founding Healion Bio, Dr. Bavari founded Edge BioInnovation Consulting and Mgt. and was the Chief Scientific Officer and Scientific Director at USAMRIID (US Army Research Institute of Infectious Diseases), where he spent over twenty years leading the discovery and development of vaccines, therapeutics, and diagnostics or diseases such as SARS and MERS CoVs, Ebola, Marburg, Zika, Smallpox, Sudan, Nipah, alpha viruses, Anthrax and many others. He has worked extensively with the FDA to successfully develop clinically proven countermeasures for many so-called envelope viruses like SARS-CoV-2. Dr. Bavari has contributed to ~20 drug development candidates such as Remdesivir, 30 patents, and many IND filings. He has trained over 70 scientists and managed over 500 scientists and supporting staff. His work has resulted in over 350 publications in many of the leading scientific journals including Nature, Nature Medicine, Cell, Cell Hosts, New England Journal of Medicine and many others. He has degrees from USC, and the University of Nebraska where he received his PhD in Immunotoxicology and Pharmaceutical Science.

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Ralph Rogers, MD

Assistant Professor of Medicine, Clinician Educator, Infectious Diseases, Warren Alpert Medical School of Brown University

Ralph Rogers, MD is an infectious disease specialist at the Lifespan Cancer Institute. He earned his medical degree from The Warren Alpert Medical School of Brown University where he also completed his residency and fellowship in infectious diseases. Dr. Rogers is Assistant Professor of Medicine, Clinician Educator Division of Infectious Diseases Warren Alpert Medical School of Brown University. He is a member of the Infectious Diseases Society of America (IDSA), the American Society for Microbiology (ASM) and the American Society of Transplantation (AST).

John Sninsky, PhD

Consultant, Translational Sciences

John J. Sninsky, PhD is a translational medicine consultant with deep understanding of diagnostics and diagnostics paired with medicine intervention. John has served in senior management positions in small and large CLIA service laboratories and in vitro diagnostic kit companies including Cetus, Roche Molecular Systems, Celera, Quest and CareDx. He was a member of the pioneering Cetus team that developed and optimized PCR technology for research and diagnostic use; specifically, the virology team developed the HIV, HTLV, HPV, HCV and HBV PCR assays. John put in place a surveillance initiative for viral variants and presented at the first FDA PMA advisory meeting for HIV PCR approval.

Timothy J. O’Leary, MD, PhD

Adjunct Professor, Pathology, University of Maryland School of Medicine; Former Chief Research and Development Officer, Veterans Affairs

Timothy O’Leary, MD, is Adjunct Professor of Pathology at the University of Maryland and served as Chief Research and Development Officer (CRADO) of the Department of Veterans Affairs from 2013-2015. He holds a doctorate in physical chemistry from Stanford University and a medical degree from the University of Michigan.

He is certified in anatomic pathology by the American Board of Pathology and in molecular genetic pathology by the American Board of Pathology and the American Board of Medical Genetics. Prior to his VA service, O’Leary chaired the Department of Cellular Pathology and Genetics at the Armed Forces Institute of Pathology for more than 15 years. He joined VA in 2004 and served as Director of Biomedical Laboratory Research and Development, Director of Clinical Sciences Research and Development, and Deputy CRADO prior to his appointment as CRADO. O’Leary also served as a reserve member of the Public Health Service Commissioned Corps from 1979 to 2010, serving two tours on active duty. His research interests include genomics, proteomics, and ultrasensitive detection of biological toxins. He has served on numerous federal panels and advisory committees, including the Health and Human Services Clinical Laboratory Improvement Advisory Committee and the Food and Drug Administration Hematology and Devices Panel. O’Leary, the holder of four patents, has authored or co-authored more than 190 journal articles and numerous book chapters and technical reports. He is a past president of the Association for Molecular Pathology and served as editor-in-chief for the Journal of Molecular Diagnostics.