The U.S., like many countries around the world, is reeling from the COVID-19 pandemic, causing significant loss of life as well as considerable uncertainty as to how small companies will survive. Fighting the SARS-CoV-2 virus needs a startup company mentality. At my small drug discovery company, each day is an emotional rollercoaster as we grind away, prepared for anything and everything. We are not only hanging on as a company, we are fighting back and pitching into the search for drugs to cure COVID-19.
How did we get here? On January 29, I was seated 20 feet away from Anthony Fauci, MD, as he delivered a brief lecture at BioThreats 2020. I’d heard him talk a few times before, but on this day his tone was unusual; he insisted that this novel coronavirus was going to be different from SARS. As he made a quick exit after 20 minutes1 I shivered. Having followed the news from China, Fauci’s address left me in no doubt that it was going to be a grim year. The U.S. government’s reaction was slow and ultimately ineffective as February 2 travel restrictions were imposed on flights from China. Many pandemic warning signs over the years, from former presidents, authors, scientists, and intelligence reports, had been missed.2
Back at my small company, Collaborations Pharmaceuticals, which works on rare and neglected diseases (including Ebola, HIV, Enteroviruses, and Zika), I started to plan for what happens next. Weeks before the official shutdown, we told our team to be ready for the worst and prepare to work from home. We put the finishing touches on manuscripts for a 50-year-old drug called tilorone, for which we had collected data on Middle East respiratory syndrome (MERS).3,4 This ultimately reached InterChem, a Ukrainian company that makes the drug and they were interested in seeing how it could be used in the pandemic.
Unlike previous outbreaks such as Ebola and Zika, we had not rushed to work on SARS-CoV-2, but that soon changed after talking with my team. We computationally docked a few FDA-approved drugs in the virus protease structure, and invited our Zika collaborators in Brazil, Carolina Andrade, and Melina Mottin, to work on them as well. After a clinician in New York, Megan Coffee, MD, PhD, reached out to ask what drugs her hospital could start stockpiling, we all prepared a manuscript with our recommendations, discussing how we could use our experience in past virus outbreaks for repurposing drugs against COVID-19.5 Little did we know how these actions literally kept our lab open because of the active work on the virus.
When the shutdown came in North Carolina on March 16, most of my colleagues took their desktop computers home, while those without any underlying health issues opted to stay to keep as many projects going as possible. Since then, our collaborator network has expanded to provide additional molecules not included in the growing list of some 200 drugs and vaccines under assessment elsewhere.6 We have collected molecules from several colleagues and sent them to three U.S. labs with in vitro testing capabilities against SARS-CoV-2 or submitted them for testing against MERS at NIAID (as they initially did not have a SARS-CoV-2 assay).
We also sent compounds to our collaborators in Brazil, who were purifying proteins and started to formulate what we could do ourselves. While we were not equipped to work with the live coronavirus, we could run tests on viral proteins to see if drugs would bind to them. My colleague Ana Puhl rented key equipment and purchased various reagents, beginning with the virus spike protein. Ana has now tested dozens of FDA-approved drugs or clinical candidates and found several that bind at nM levels. These compounds have been prioritized for other in vitro testing against the virus in human cells and we look forward to sharing our results in due course.
Flooded with reports
As preprint servers were flooded with reports from labs around the world, we pulled them together and applied a machine learning model. Our Brazilian intern, Victor Gawriljuk, switched from a project on yellow fever virus to use machine learning to model SARS-CoV-2. Ultimately, we made these models public and update them weekly. This caught the eye of a big pharma and other researchers, and we’re providing free access to help them with their own repurposing efforts.
The COVID-19 field is moving so fast that sometimes the work is done by others while we are waiting for the virus testing. An antimalarial drug called pyronaridine was one of our highest priority compounds to test and a recent preprint from The Institut Pasteur Korea showed some activity.7 However that study used Vero Cells, whereas our recently published Ebola work showed this compound is selectively cytotoxic in these cells relative to human cells such as Hela.8 This attracted attention of the company that makes it, Shin Poong Pharm, and it is now in a Phase II trial in South Korea.
Much of my time lately has been devoted to writing grant proposals or submitting paperwork on compounds to NIAID or DARPA as they each requested ideas. This highlights the lack of coordination between government agencies. In many cases, we have heard nothing in the two months since submitting our application. As a small biotech, we cannot lobby to get our products or ideas in front of government decision makers, like the dream team of scientists involved in Scientists to Stop COVID-19.9
The slow response on getting NIH funding out to labs is just another sad indicator of the rampant disorganization surrounding the pandemic response. Request for applications were slow in coming and I imagine it will be months before review and funding decisions are made. Americans and the world are now dealing with the consequences of our government’s inaction. We will be picking up the pieces scientifically, emotionally, and financially for decades to come.
Cause and effect
The chaos surrounding this pandemic is forcing scientists like us that want to work on the virus to get creative and have to do it all ourselves, because of a complete lack of free and centralized resources to tap into. Fortunately, we have a strong collaborator network from our years working on infectious diseases. Without Fedex and UPS, our collaborative efforts would be impossible. I’m sure others are facing similar issues.
Not only are we working on this virus, we are also trying to keep the lights on by working on our other government-funded (NIH, DTRA) projects, while engaging clients to perform fee-for-service machine learning work. Sure, our research efforts against this virus are modest by comparison to many others, but we’re not a major pharma or academic institute. Perhaps if philanthropists like a Gates, Milken, or Thiel were to support smaller companies like us in these efforts their influence would help catalyze progress, bring us to the attention of government agencies and keep our scientists employed.
We may be a footnote in finding a cure for COVID-19, but I am thankful for my team and our growing family of global collaborators, who continue to keep me energized and inspired in their efforts to vanquish the virus, perhaps the biggest challenge of our lifetime.
1. Anon. Anthony Fauci Addresses Coronavirus 2020.
2. Davies K. Blinking Red: 25 Missed Pandemic Warning Signs 2020.
3. Ekins S, Lane TR, Madrid PB. Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond. Pharm Res. 2020;37(4):71.
4. Ekins S, Madrid PB. Tilorone: A Broad-Spectrum Antiviral For Emerging Viruses. Antimicrobial agents and chemotherapy. 2020;IN Press.
5. Ekins S, Mottin M, Ramos P, Sousa BKP, Neves BJ, Foil DH, Zorn KM, Braga RC, Coffee M, Southan C, Puhl AC, Andrade CH. Déjà vu: Stimulating open drug discovery for SARS-CoV-2. Drug Discov Today. 2020.
6. Philippidis A. Vanquishing the Virus: 160+ COVID-19 Drug and Vaccine Candidates in Development 2020.
7. Jeon S, Ko M, Lee J, Choi I, Byun SY, Park S, Shum D, Kim S. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs 2020.
8. Lane TR, Massey C, Comer JE, Anantpadma M, Freundlich JS, Davey RA, Madrid PB, Ekins S. Repurposing The Antimalarial Pyronaridine Tetraphosphate To Protect Against Ebola Virus Infection PLoS Negl Trop Dis. 2019;13:e0007890.
9. Copeland R. A Manhattan Project for Covid-19 The Journal 2020.