By Peter B. Madrid, Ph.D., VP SRI Biosciences, SRI International
Every virus is different — but by finding small similarities in their genomes, we can develop treatments that will make us more prepared for future outbreaks
As COVID-19 began sweeping across the globe this year, scientists raced to develop diagnostic tests, vaccines and treatments. Unfortunately, because we’ve had no experience identifying, preventing or treating this specific virus, it had a tremendous head start. If COVID-19 was a marathon, the virus was already miles ahead when we began running.
Individual viruses are one of the ultimate surprises that nature throws at us. They are constantly evolving alongside animals — including humans — meaning that new ones are emerging all the time. In addition, no two viruses are exactly alike. At a genetic level, viruses are incredibly diverse in the ways they copy themselves and spread.
This has made it particularly difficult for scientists to develop drugs and vaccines that work against more than one viral disease. Vaccines are usually highly specific for a given type of virus and can even vary widely in effectiveness against different virus strains. Approved drugs that target unique enzymes and receptors used by viruses to invade host cells and replicate can be very effective, but will probably have very little (or no) effect whatsoever on coronaviruses, including the Severe Acute Respiratory Virus coronavirus (SARS-CoV) strain that is now killing thousands of people around the world.
Fortunately, research conducted over the past five decades has revealed that there are often at least a few small pieces of viral machinery that are consistent or at least structurally similar across many viruses. These common pieces — part of the virus’ genomic make-up — are usually enzymes or proteins that are essential for the viruses to replicate (or even to survive). If we develop a treatment that targets and blocks these enzymes or proteins in one virus, it may make it easier for us to get a leg up on any new viruses that have this same genomic machinery.
We’ve done this before. Today, there are two classes of drugs — known as viral polymerase inhibitors and viral nuclease inhibibors — that are used to treat multiple viral infections, including human immunodeficiency virus (HIV), influenza, hepatitis B and herpes simplex virus. Viral polymerases are enzymes that stitch together sequences of either DNA or RNA to help the virus replicate itself. Viral nucleases, on the other hand, are the scissors; they are enzymes that chop up DNA or RNA to enable replication or, in some cases, to hide from the host’s immune system. Not all of the drugs that target these viral enzymes will work against new emerging viruses, but this is the first place to start looking for solutions. Remdesivir, an experimental nucleoside analog that was being investigated for use in people with the Ebola virus, has now been shown to help people with COVID-19 recover from their illness. This is likely because — while the Ebola and SARS genomes are generally very different — both contain an enzyme with a similar function and binding site.
Since the first SARS-CoV outbreak in 2002–2003, scientists have studied this virus extensively. Comparing the genomic sequences from the new virus identified in 2019 (now known as SARS-CoV-2), we’ve learned that it is closely related to SARS-CoV. In fact, there is one particular gene sequence in SARS-CoV — known as non-structural protein 15 (nsp15) — that has 95.7 percent similarity to a gene sequence in the SARS-CoV-2 virus.
Studies looking at the sequence and structure of nsp15 suggest that it is an endonuclease, a type of enzyme that plays an essential role in the development of disease, and that it is structurally similar among multiple coronaviruses. Additionally, this endonuclease protein is highly likely to perform the same function in these coronaviruses, helping them protect themselves from the human immune system. A drug that inhibits nsp15, therefore, could be an effective treatment againsts SARS-CoV, SARS-CoV-2 and any new, emerging coronaviruses.
While there are currently no FDA-approved drugs that target this particular endonuclease, there is a successful track record for developing antiviral drugs that inhibit other viral nucleases. The FDA recently approved the first endonuclease inhibitor (balxavir marboxil) as a treatment for the influenza A virus. In addition, there are two FDA-approved drugs, raltegravir and evitegravir, that target the HIV nuclease enzyme (called HIV integrase). Although there may be limited genetic sequence similarity between these two viruses, their nuclease enzymes all have related functions and binding sites, which gives drug researchers a headstart for developing new antiviral nuclease inhibitors.
SRI has an ongoing program focused on discovering endonuclease inhibitors, particularly on creating compounds that will be effective against potentially pandemic and drug-resistant strains of influenza. This work has led to the discovery of new chemical structures that inhibit the influenza endonuclease enzyme. These drug candidates are now being evaluated for their potential to treat multiple viruses.
Recently, we announced a collaboration with Iktos that will pair our fully automated synthetic chemistry system, SynFini, with Iktos’ artificial intelligence technology to speed up the discovery and optimization of new endonuclease inhibitors. We are hopeful that combining our leading automation and AI systems will result in new antiviral drugs that are — initially — effective against influenza and SARS-CoV-2.
Ultimately, given the presence of nuclease enzymes across almost all types of viruses, we believe these inhibitors will help us to be more prepared to win the race against future viral outbreaks.
