Betulinic acid derivatives as inhibitors of SARS-CoV-2 entry into target cells

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel coronavirus that is responsible for the COVID-19 pandemic. The main symptoms of COVID-19 are shortness of breath, fever, and pneumonia, which can be fatal in vulnerable individuals. Since the beginning of the pandemic, research groups all over the world applied for developing new prophylactic and pharmacological treatments specific for SARS-CoV-2. Up to now, nine vaccines have been approved by the World Health Organization (WHO) for emergence use in many countries. Even if the efficacy of these vaccines has been demonstrated by many clinical trials, many issues associated with the distribution and administration of the vaccines themselves emerged. Therefore, it became clear that vaccination campaign alone was not enough to stop SARS-CoV-2 spreading around the world. Several antiviral and immunomodulatory drugs commonly used in clinical practice to treat viral infections have been proposed by WHO for emergence use: however, clinical trials demonstrated that most of these treatments are not applicable to SARS-CoV-2. Therefore, there still is the need to identify new drugs suitable for the treatment of COVID-19. In this experimental work, the anti-SARS-CoV-2 activity of betulinic acid, glycyrrhetinic acid and novel experimental compounds (FS11, FS37, LP11, LP14, LP50, LP51) has been evaluated through a system based on HIV-derived recombinant lentiviral particles pseudotyped with the SARS-CoV-2 S protein. Since the S protein has been demonstrated to be necessary and sufficient for allowing SARS-CoV-2 entry into susceptible cells, lentiviral pseudotyped particles potentially represent an ideal tool for evaluating the activity of candidate entry inhibitors without being affected by the limitations intrinsic of live virus.