Targeting COVID-19

Weizmann scientists are advancing 60-plus projects related to coronavirus

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Briefs

November 10, 2020

Since the global coronavirus outbreak began, Weizmann Institute scientists have been working diligently to apply their expertise in life sciences, chemistry, physics, computer sciences, and artificial intelligence to find solutions for new testing methods, unique tracking solutions, and devising potential drugs and vaccines. Others are looking at the mental health effects of the pandemic. All in all, more than 60 projects are ongoing on campus related to the urgent hunt for understanding and solutions. Generous donors throughout the world have supported this research through the Weizmann Coronavirus Response Fund.

Here is a snapshot of just a few of the many ongoing Weizmann projects aimed at overcoming the COVID-19 challenge.

Screening and diagnosis

Prof. Ido Amit and Prof. Eran Elinav in the Department of Immunology and their teams have collaborated to develop a radically improved system—meaning, safer and faster—for screening individuals for SARS-CoV-2 infection. The process includes the use of specially designed swabs and a “one-step” buffer that both neutralizes the virus (so that it's not alive, but its presence can be tested for) and allows for direct screening of the samples with no further required genetic extraction steps. Since the technology is based on next-generation sequencing, samples can be pooled such that screening can be performed in parallel and massively scaled up for tens of thousands of individuals a day. Any positive samples can then be winnowed down and re-tested for confirmation without concern about cross-contamination.

The system uses advanced microfluidics and robotic systems that improve both reproducibility and accuracy, while also reducing risk to technicians and labor requirements. The system also uses AI methods for both diagnostic and prognostic applications.

The testing pipeline has already been performed on thousands of samples, in collaboration with Israel’s Ministry of Defense, Ministry of Health, and various hospitals nationwide.

The hunt for drug options

Dr. Nir London from the Department of Organic Chemistry and the COVID ‘Moonshot’ consortium he spearheded is experimenting with a new way to discover drugs: crowdsourcing ideas, eliminating intellectual property, and involving every key player in the long drug-discovery process—from biotech companies to contract research organizations—from the get-go, to expedite development. Following a screening sprint in February, Dr. London and colleagues released all of their data to the public. In March, they posted a request to medicinal chemists worldwide to use this data and suggest designs for a molecule that might inhibit a main coronavirus enzyme, called a protease. The effort has generated more than 10,000 design ideas from more than 350 contributors. The consortium synthesized more than 1,000 compounds, tested their activity, and are homing in on the most promising possibilities.

Diamond Light Source—the UK’s national synchrotron facility—helped refine the short list of the best inhibitory molecules by determining their structure. To date, the Moonshot team has identified several series of compounds that are potent at low doses at combatting the virus. In an illustration of the widespread collaborative spirit this outbreak has engendered among scientists, the resultant data are made public in real-time—precluding competition to publish and providing a clear blueprint for further optimizing these compounds.

The project is now nearing its next stage: focusing on the three best-performing series of candidates to take into pre-clinical assessment in animal models, and ensuring safety, efficacy, and stability.

The consortium demonstrates that there’s more than one way to run a drug discovery pipeline—and this is an alternative that can be implemented against the unmet medical needs of the future.

In parallel, the high-throughput screening unit at the Weizmann Institute’s Nancy and Stephen Grand Israel National Center for Personalized Medicine, led by Dr. Haim Barr, screened 200,000 pre-existing compounds from the Grand Center’s library against the protease. Approximately 135 of these compounds warranted follow-up, including analysis by the Diamond Light Source.

Existing drugs, new purposes

For many years, Prof. Emeritus Yosef Shaul has studied virus-host cell interactions, with a focus on the hepatitis B virus (HBV). These investigations have shown how HBV, with its limited genetic content, can invade cells and occupy its host’s relevant cellular machinery. He developed a highly effective vaccine for HBV. He now plans to re-purpose a compound approved by the U.S. Food and Drug Administration (imatinib, sold under the brand name Gleevec) to inhibit SARS-CoV-2 infection.

In previous studies, researchers have reported that imatinib can be effective against the 2003 severe acute respiratory syndrome (SARS) virus as well as the 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) in cell culture.  The Shaul lab’s preliminary data—collected in collaboration with the Israel Institute for Biological Research—demonstrate that imatinib markedly inhibits SARS-CoV-2 infection,in nearly all cases by preventing virus/cell membrane fusion, a critical step in the entry of a virus into a healthy cell. Given this dramatic effect and its proven satisfactory safety profile, Prof. Shaul believes that imatinib may be an effective drug for treating COVID-19.

Tricking the virus

Immunotherapy for COVID-19 is one of the most promising clinical approaches for treating patients and improving their outcomes. In his two-pronged project, Dr. Ron Diskin of the Department of Structural Biology—an expert in lethal animal-borne viruses like Ebola—is working to devise a ‘decoy’ molecule that will allow healthy cells to evade SARS-CoV-2, and find an antibody that accurately binds to it.

With its expertise in the interplay among viruses, hosts, and the immune system, the Diskin group recently developed a broad-spectrum and highly potent decoy (an ‘immunoadhesin’) against a class of viruses known as arenaviruses. They now are using that same technique to develop an immunoadhesin against coronaviruses, and SARS-CoV-2 in particular. They have focused on outwitting a specific cellular receptor (ACE2) that the virus binds to in order to gain entry to a cell. Using a computational algorithm, the group has had much success modeling the structure of the ideal decoy immunoadhesin—one with unprecedented potency, which they named “Coronacept”.

Encouraged by these exceptional results, Dr. Diskin and his team are now finalizing the biological design of Coronacept, with the hope of partnering with a pharmaceutical company for advanced pre-clinical development.

Slipping through the defenses

Prof. Sarel Fleishman of the Department of Biomolecular Sciences and his team are applying a unique platform he developed in his lab—that has already led to a candidate for a potential malaria vaccine—to the coronavirus. This involves the design of millions of “nanobodies”—small synthetic antibodies that could possibly slip through the coronavirus’s formidable defenses. Prof. Fleishman hopes to home in on the most effective ones as possible drug candidates.

Since the first molecular structures of the so-called SARS-CoV-2 spike protein were published in early March 2020, the Fleishman lab has focused on targeting their nanobodies to specific sites on the spike protein. The ability to bind to these sites would indicate a powerfully effective inhibitor—one resistant to the emergence of viral mutations. (Viral mutations account for why flu vaccines must be redesigned each year.)

The Fleishman lab designed and tested two million nanobodies; a very small fraction bound to the spike protein. The lab is now optimizing these antibodies’ affinity and in parallel, computing additional versions for experimental testing.

Prof. Fleishman is also collaborating with the Israel Institute for Biological Research to test the effectiveness of recovered COVID-19 patients’ antibodies to inhibit SARS-CoV-2 infection in others.

Looking at the lungs

Doctors treating COVID-19 patients have seen widespread evidence of the effect of the disease in images of the lungs. While CT scans are considered the best imaging option, they are expensive and non-portable, and it is complicated and time-consuming to disinfect CT scanners between patients. Most hospitals use X-ray machines to image the lungs of COVID-19 patients, as it is cheaper, more accessible, and easier to disinfect, but the results are often ambiguous. Ultrasound is portable and relatively easy to disinfect, but it is not widely used as a lung diagnostic tool.

Prof. Yonina Eldar of the Department of Computer Science and Applied Mathematics and her lab group are tackling this problem by assembling a uniquely diverse and extremely talented team of Weizmann life scientists and machine learning and data science experts, a volunteer squad of data science experts from Israeli companies, as well as hospital physicians across Israel who are already participating in a clinical forum Prof. Eldar heads. The group aims to develop and implement image analysis techniques, using AI that will help with the identification, triage, and diagnosis of COVID-19 patients and suspected carriers, using X-ray and ultrasound. These methods will also be used to monitor disease progression and prognosis as well as to monitor patients post-disease.

Early findings show 90% accuracy in diagnosing patients admitted to hospitals, which far surpasses the detection rate of the standard blood-based genetic tests (currently at 70% success for virus carriers), and the speed of obtaining results (minutes versus hours or days). This work paves the way for using X-ray and ultrasound as diagnostic tools outside hospitals—at a community clinic, for example.

This research is possible thanks to generous donor support:

Prof. Ido Amit's research is supported by the Adelis Foundation; Thomas Franklin Buchheim; Rosanne Cohen; Ben B. and Joyce E. Eisenberg Foundation given by Joyce Eisenberg Keefer; Mauricio Gerson; Kekst Family Institute for Medical Genetics; Helen and Martin Kimmel Award for Innovative Investigation; Lowy Foundation; Lady Michelle Michels; Erika Mogyoros; Jeff Pinkner and Maya Iwanaga; Estate of Arthur Rath; Anita James Rosen Foundation; Sagol Institute for Longevity Research; Estate of Simon Saretzky; Richard & Jacqui Scheinberg; Thompson Family Foundation Alzheimer's Research Fund; Vainboim Family; Wolfson Family Charitable Trust; Prof. Amit is the incumbent of the Eden and Steven Romick Professorial Chair.

Dr. Haim Barr's research is supported by the Maurice and Vivienne Wohl Institute for Drug Discovery.

Dr. Ron Diskin's research is supported by the Ernst I Ascher Foundation; Ben B. and Joyce E. Eisenberg Foundation given by Joyce Eisenberg Keefer; Estate of Emile Mimran; Jeanne and Joseph Nissim Center for Life Sciences Research; Dov and Ziva Rabinovich Endowed Fund for Structural Biology; Marcia and Donald Rivin; Stanley and Tanya Rossby Endowment Fund; Natan Sharansky/MATAN Foundation; Dr. Barry Sherman Institute for Medicinal Chemistry; Dr. Diskin is the incumbent of the Tauro Career Development Chair in Biomedical Research.

Prof. Yonina Eldar's research is supported by the Benoziyo Endowment Fund for the Advancement of Science; Brenden-Mann Women’s Innovation Impact Fund; Jean and Terry de Gunzburg; Manya Igel Centre for Biomedical Engineering and Signal Processing; Olga Klein – Astrachan; Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics.

Prof. Eran Elinav's research is supported by the Adelis Foundation; Harold Altman Charitable Trust; Alex Davidoff; Ben B. and Joyce E. Eisenberg Foundation given by Joyce Eisenberg Keefer; Leona M. and Harry B. Helmsley Charitable Trust; Morris Kahn Institute for Human Immunology; Else Kroener Fresenius Foundation; Hanna and Dr. Ludwik Wallach Cancer Research Fund; Howard and Nancy Marks Charitable Fund; Daniel Morris Trust; Jeanne and Joseph Nissim Center for Life Sciences Research; Lawrence and Sandra Post Family Foundation; Dr. John L. and Vera Schwartz; Yael and Rami Ungar; Vainboim Family; Pearl Welinsky Merlo Scientific Progress Research Fund; White Rose International Foundation; European Research Council; Prof. Elinav is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair of Immunology.

Prof. Sarel-Jacob Fleishman's research is supported by the Ben B. and Joyce E. Eisenberg Foundation given by Joyce Eisenberg Keefer; Darlene Switzer-Foster and Bill Foster; Henri Gutwirth Fund for Research; Stanley and Ellen Magidson; Milner Foundation; Schwartz/Reisman Collaborative Science Program; Dr. Barry Sherman Institute for Medicinal Chemistry; Dianne and Irving Kipnes Foundation, Carolyn Hewitt and Anne Christopoulos, in Memory of Sam Switzer; Sam (Ousher) Switzer & Children; Yeda-Sela Center for Basic Research; European Research Council.

Dr. Nir London's research is supported by the Estate of Emile Mimran; Moross Integrated Cancer Center; Rising Tide Foundation; Honey and Dr. Barry Sherman Lab; Dr. Barry Sherman Institute for Medicinal Chemistry; Nelson P. Sirotsky; Dr. London is the incumbent of the Alan and Laraine Fischer Career Development Chair.

Prof. Emeritus Yosef Shaul's research is supported by the Jean - Jacques Brunschwig Fund for the Molecular Genetics of Cancer; Leo and Julia Forchheimer Center for Molecular Genetics; Sergio Lombroso Award in Cancer Research; Moross Integrated Cancer Center; David M. Polen Charitable Trust.