The Pandemic Issue

disinfectant. The tale illustrates both the unanticipat- ed difficulties of drug development and that one never knows how knowledge ultimately might be put to use. Remdesivir is a failed drug for Ebola that has found new life with SARS-CoV-2. It targets polymerase, an enzyme that the virus produces to use host cell machinery to replicate itself, and since the genetic se- quence of polymerase is very similar among all of the different coronaviruses, scientists hope that the drug might be useful against known members of the family and others that might emerge in the future. But nature isn’t always that simple. Viral RNA is not a two-dimensional assemblage of genes in a flat line on a table; rather it is a three-dimensional matrix of twists and turns where a single atom change within the polymerase gene or another gene close by might change the orientation of the RNA or a molecular arm within it and block a drug from accessing the targeted binding site on the virus. One drug might need to bind to a large flat surface, while another might be able to slip a dagger-like molecular arm through a space in the matrix to reach its binding target. That is why a broad-spectrum antiviral is so hard to develop, and why researchers continue to work on a wide variety of compounds that target polymerase as a binding site. Additionally, it has taken us decades to begin to recognize the unintended consequences of broad- spectrum rather than narrowly targeted antibiotics on the gut microbiome and our overall health. Will a similar issue potentially arise in using a broad- spectrum antiviral? “Off-target side effects are always of concern with drugs, and antivirals are no exception,” says Yale University microbiologist Ben Chen. He believes that “most” bacteriophages, the viruses that infect bacteria and likely help to maintain stability in the gut micro- bial ecosystem, will shrug off such a drug. However,

a few families of phages share polymerases that are similar to those found in coronaviruses. While the immediate need for treatment is great, we will have to keep a sharp eye out for unanticipated activity in the body’s ecosystem from new drugs. Is an Antiviral Needed? There are many unanswered questions about COVID-19, but perhaps the most fascinating is wheth- er we even need to directly go after the virus itself. Mounting evidence indicates that up to half the people who contract the infection don’t seem to experience significant symptoms and their immune system seems to clear the virus. The most severe cases of COVID-19 appear to result from an overactive immune response that damages surrounding tissue. Perhaps downregulating that re- sponse will be sufficient to reduce the disease burden. Several studies are underway using approved antibod- ies that modulate an overly active immune response. One of the most surprising findings to date involves the monoclonal antibody leronlimab. It was originally developed to treat HIV infection and works modestly well there, but other drugs are better and its future likely will be mainly to treat patients who have devel- oped resistance to those other drugs. The response has been amazingly different in patients in the U.S. with COVID-19 who were given emergency access to leronlimab – two injections a week apart, though the company believes that four might be bet- ter. The immune response and inflammatory cytokines declined significantly, T cell counts were maintained, and surprisingly the amount of virus in the blood de- clined too. Data from the first ten patients is available in a preprint while the paper undergoes peer review


Would a Broad-Spectrum Antiviral Drug Stop the Pandemic?


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