Wearing blue surgical gowns and white respirator hoods, research scientist Pradeep Uchil and post-doctoral fellow Irfan Ullah carry an anesthetized mouse to the lab’s imaging unit. Two days ago, the mouse was infected with a SARS-CoV-2 virus engineered to produce a bioluminescent protein. After an injection of a bioluminescence substrate, a blue glow starts to emanate from within the mouse’s nasal cavity and chest, visible to the imaging unit’s camera and Uchil’s eyes.
“We were never able to see this kind of signal with retrovirus infections.” Uchil is a research scientist at the Yale School of Medicine whose work focuses on the in vivo imaging of retroviral infections. Normally, the mouse would have to be sacrificed and “opened up” for viral bioluminescent signals from internal tissues to be imaged directly.
A year after COVID-19 was declared a pandemic, collaborative efforts among pharma/biotech and academic researchers have led to remarkable progress in vaccine development. These efforts include novel mRNA vaccine technology, as well as more conventional approaches using adenoviral vectors. While vaccine deployment understandably has captured the spotlight in the fight against COVID-19, there remains an urgent need to develop therapeutic agents directed against SARS-CoV-2.
In the March 12 issue of Science, an editorial by Dr. Francis Collins, director of the U.S. National Institutes of Health (NIH), examines lessons learned over the past 12 months (1). Collins points out that many clinical trials of potential therapeutics were not designed to suit a public health emergency. Some were poorly designed or underpowered, yet they received considerable publicity—as was the case with hydroxychloroquine. Collins advises developing antiviral agents targeted at all major known classes of pathogens, to head off the next potential pandemic before it becomes one. A news feature in the same issue discusses the current state of coronavirus drug development (2).
The present crop of drug candidates is remarkably diverse, including repurposed drugs that were originally developed to treat diseases quite different from COVID-19. Typically, however, the mainstream candidates belong to two broad classes: small-molecule antiviral agents and large-molecule monoclonal antibodies (mAbs).
COVID-19 vaccine distribution efforts are underway in several countries. Recently, the Serum Institute of India celebrated the nationwide rollout of its Covishield vaccine, kicking off the country’s largest ever vaccination program. Meanwhile, many other vaccines against the coronavirus that causes COVID-19 are in either preclinical studies or clinical trials. At present, 19 vaccine candidates are in Phase 3 clinical trials, while 8 vaccines have been granted emergency use authorization (EUA) in at least one country.
The global war against the coronavirus that causes COVID-19 rages on, spearheaded by efforts to develop effective and safe vaccines. At the time of writing, over 100 COVID-19 vaccine clinical trials were listed in the clinicaltrials.gov database. Recent attention has focused on mRNA vaccines developed by Pfizer/BioNTech and Moderna. If licensed, they would become the first mRNA vaccines for human use.
The SARS-CoV-2 nucleocapsid protein accounts for the largest proportion of viral structural proteins and is the most abundant protein in infected cells. Nucleocapsid proteins have the job of “packaging” the viral nucleic acid (in this case, RNA). Viral nucleocapsid proteins can also enter the host nucleus and interact with a variety of host proteins to interfere with critical processes of the host cell, including protein degradation. Here we review a study that used an in vitro protein degradation assay to investigate the interaction of the SARS-CoV-2 nucleocapsid protein and the proteasome activator PA28γ.
In SARS-CoV-2 infections, the nucleocapsid protein is critical for infection, replication and packaging. The SARS-CoV-2 nucleocapsid protein is not only localized in the cytosol of the host cell but also is translocated into the nucleus. There, it interacts with various cellular proteins that modulate cellular functions, such as the degradation of unneeded or damaged proteins by proteolysis. Researchers have proposed that the protein degradation system plays an important part in coronavirus infection (1).
This post was written by guest blogger, Nitin Kapoor, from our Promega India branch office.
The COVID-19 crisis has led to substantial worldwide efforts to develop drug treatments and vaccines effective against SARS-CoV-2. Termed a novel Coronavirus, SARS-CoV-2 belongs to the same family as that of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) viruses that were responsible for epidemics in 2003 and 2012 respectively (Lu et al. 2020)
In the nine months since the first cases of COVID-19 were noticed in Wuhan, China, the virus has spread around the globe and infected over 22 million people. As with all emerging infectious diseases, we often find ourselves with more questions than answers. However, through the tireless work of researchers, doctors and public health officials worldwide, we have learned a lot about the virus, how it spreads and how to contain it.
With the COVID-19 pandemic far from over in the United States and worldwide, the battle against the disease continues to intensify. Much hope has been pinned on vaccine development. However, vaccines are a long-term, preventative strategy. The immediate need for drugs to fight COVID-19 has accelerated efforts for a variety of potential treatments (see The Race to Develop New Therapeutics Against Coronaviruses).
The Remdesivir Origin Story
One drug that has received widespread attention is remdesivir. It was developed from research by Gilead Sciences that began in 2009, originally targeting hepatitis C virus (HCV) and respiratory syncytial virus (RSV) (1). At present, remdesivir is classified as an investigational new drug (IND) and has not been approved for therapeutic use anywhere in the world.
Many research labs around the world have temporarily closed their doors in response to the COVID-19 pandemic, while others are experiencing unprecedented need for reagents to perform viral testing. This urgency has led many scientists to make new connections and build creative, collaborative solutions.
“In labs that are still open for testing or other purposes, there’s certainly heightened anxiety,” says Tony Vanden Bush, Client Support Specialist. “I feel that right now, I need to help them deal with that stress however possible.”
Last week, Tony was contacted by a lab at the University of Minnesota that was preparing to serve as a secondary COVID-19 testing facility for a nearby hospital lab. The two labs needed to process up to 6,000 samples per day, and the university lab was far short of that capacity.
This blog is written by guest blogger, Heather Tomlinson, Director of Clinical Diagnostics at Promega.
Finding safe and effective treatments for human diseases takes time. Medication and diagnostic tests can take decades to discover, develop and prove safe and effective. In the United States, the FDA stands as the gold-standard gatekeeper to ensure that treatments and tests are reliable and safe. The time we wait in review and clearance means less risk of ineffective or unsafe treatments.
And yet, in a pandemic, we are behind before we even start the race to develop diagnostic tests, so critical for understanding how an infectious disease is spreading. That is when processes like the FDA’s fast track of Emergency Use Authorization (EUA) are critical. Such authorization allows scientists and clinicians to be nimble and provide the best possible test protocol as quickly as possible, with the understanding that these protocols will continue to be evaluated and improved as new information becomes available. The EUA focuses resources and accelerates reviews that keep science at the fore and gets us our best chance at staying safe and healing.
For scientists working around the clock, the FDA’s EUA process is ready to review and respond. Getting an EUA gives clinical labs a very specific and tested resource to guide them to the tools and tests to use in a crisis.
Typically the Centers for Disease Control (CDC) will develop the first test or protocol that receives FDA EUA in response to a crisis like a pandemic. For COVID-19 the CDC 2019-Novel Coronavirus Real-Time RT-PCR Diagnostic Panel received FDA EUA clearance in early February. This is the test protocol used by the public health labs that work with the CDC and test manufacturers around the world.
Throughout a crisis such as the current pandemic, scientists continually work to improve the testing protocols and add options to the EUA protocols. This enables more flexibility in the test protocols. Promega is fortunate to play a part of the CDC EUA equation for diagnostic testing. Our GoTaq® Probe 1-Step PRT-qPCR System is one of a few approved options for master mixes in the CDC qPCR diagnostic test, and now our medium-throughput Maxwell 48 Instrument and Maxwell Viral Total Nucleic Acid Purification Kit have been added to the CDC protocol as an option for the RNA isolation step as well. These additions to the CDC EUA means that laboratories have more resources at their disposal for the diagnostic testing which is so critical to effective pandemic response.
The Emergency Use Authorization provides the FDA guidance to strengthen our nation’s public health during emergencies, such as the current COVID-19 pandemic. The EUA allows continual improvement of an authorized protocol through the collaborative efforts scientists in all academia, government and industry to identify and qualify the most reliable technologies and systems, giving labs more flexibility as new products are added as options.
Dr. Tomlinson is the Director for the Global Clinical Diagnostics Strategic Business Unit at Promega Corporation with over 15 years of experience in clinical diagnostic test development. She is responsible for leading the team that drives strategy in the clinical market for Promega. Her background is in infectious disease diagnostic testing, with a focus on HIV drug resistance and evolution. Her recent work has been in oncology companion diagnostic test development. Heather has is an accomplished international presenter, delivering conference presentations in the United States, Europe, Asia, and Africa.
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