Small molecule antivirals - Still our best hope for a cure.

The non-stop daily coverage of the global race for a vaccine would lead one to believe that it is only a matter of time until one or more of the 321 vaccines being developed will be available to solve the SARSCoV-2/COVID-19 crisis. Many of us are of a different opinion. There is no guarantee that an effective vaccine will be discovered, much less available in the quantities needed to vaccinate the entire world in a timely manner. Many of us are of the opinion that a directacting antiviral, or even more likely, a cocktail of direct-acting antivirals, will transform COVID-19 from a potential death sentence to an easily treatable, mild infection that can be properly managed with minimal disruption. Vaccine development has been notoriously unpredictable. Despite decades of research, there is still no vaccine to prevent many serious viruses such as HIV/ AIDS, dengue, Zika, or norovirus (the “cruise ship” virus), among many others. Even vaccines that are available have limitations the annual flu shot is often rendered ineffective because of viral mutations and the numerous strains that circulate each year. Moreover, vaccines are not particularly stable, they require critical infrastructure and human know-how from production to application, and they take a long time to develop, even under accelerated conditions. Most antivirals can be orally self-administered, are stable, and typically straightforward to make. In addition, the immunocompromised, those with underlying health conditions, or who are allergic to the vaccine components cannot get a vaccine. Thus, even if a vaccine is developed, many people will not be able to take it, thus leaving them vulnerable to infection. Antivirals have been highly successful against many viruses; i.e, the numerous drug cocktails developed for HIV/AIDS and HCV are so effective that HIV can remain at undetectable levels for a patient’s entire lifetime, and HCV is now cured in a few weeks in 98% of infected patients. There are currently >20 FDA-approved cocktails available to treat HIV/AIDS that include 2–4 direct-acting drugs. This approach has been highly successful because it is difficult to completely shut down viral replication with only one drug, and because of this, resistance is selected for. As a result, most indications require two or more drugs to successfully reduce the selection for resistance. While the search for a cure continues, there remain concerns among many that just too much attention and funding is focused on vaccines, while ignoring small molecule antivirals. We find ourselves scrambling for a cure today because many funding agencies considered the two previous CoV outbreaks (SARS and MERS) as isolated events unlikely to affect many. As a result, funding for research on CoV antivirals was scarce at best. Clearly that consideration has proven incorrect, and one can argue that it was a fatal mistake for those we’ve lost. As we all work to find answers to this deadly pandemic, it is important not to repeat those mistakes, and to be prepared for future outbreaks. Given the successes of antivirals, it is critical they are not overlooked in the understandable rush to develop vaccines.