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The global COVID-19 pandemic is underway. In recent weeks, several countries throughout the globe, and particularly in Europe, have experienced an exponential increase in the number of individuals infected with COVID-19, probably induced by a new variant of SARS-CoV-2, called the “Omicron variant.” Mass vaccination against COVID-19 continues worldwide. Are authorized mRNA vaccines effective against the new Omicron variant? Recently, several pharmaceutical companies have developed oral antiviral pills against SARS-CoV-2, i.e., molnupiravir and paxlovid, that inhibit SARS-CoV-2 viral replication by acting on the RNA polymerase of SARS-CoV. In pre-registration clinical trials, molnupiravir and paxlovid have shown excellent clinical efficacy results, but what impact will these new oral antiviral agents have against pandemic COVID-19? In what specific clinical situations are they preferred over other antivirals such as remdesivir? In this brief review, we explore these important aspects. Graphical abstract: [Figure not available: see fulltext.]

In March 2019, the global COVID-19 pandemic caused by the novel SARS-CoV-2 coronavirus began. The first cases of SARS-CoV-2 infection occurred in November 19 in Wuhan, China. Preventive measures taken have not prevented the rapid spread of the virus to countries around the world. To date, there are approximately 3 million deaths, and a massive worldwide vaccination campaign has recently begun. SARS-CoV-2 uses the ACE-2 protein as an intracellular carrier. ACE-2 is a key component of the renin-angiotensin system (RAS), a key regulator of cardiovascular function. Considering the key role of ACE-2 in COVID-19 infection, both as an entry receptor and as a protective role, especially for the respiratory tract, and considering the variations of ACE-2 during the phases of viral infection, it is clear the important role that pharmacological regulation of RAS and ACE-2 may take. In this article, we describe the importance of ACE-2 in COVID-19 infection, the pharmacological aspects of a modulation with RAS-modifying agents, new therapeutic strategies, trying to provide a deep understanding and explanation of the complex mechanisms underlying the relationship between the virus and ACE-2, providing opinions and personal hypotheses on the best strategies of therapeutic intervention.