The new Severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2) triggered the pandemic of COVID-19, which is currently still ongoing. In 2021 a worldwide vaccine campaign was launched, and in parallel the lines of research are continuing to target the most effective drug therapies for the treatment of COVID-19 disease. SARS-CoV‑2 enters host cells via glycoprotein angiotensin-converting enzyme 2 (ACE-2), which plays a major role in renin-angiotensin system interactions and undergoes changes in expression during metabolic and viral diseases, including COVID-19. It seems that the severe lung damage that occurs in several cases of COVID-19 disease may be connected to a deregulated expression of ACE‑2. In this manuscript we focus on the line of research that studies the pharmacological modification of ACE‑2 expression, a promising weapon to counter the severe harms caused by COVID-19.