Repurposing drugs to fight COVID-19: SARSCoV- 2 envelope targeting by clinically approved porphyrins and analogues

Despite mitigation measures and vaccination programs, there are still very few medicines to treat COVID-19. Porphyrins and analogues (P&A) usually present broad-spectrum antiviral activity. Some are clinically approved for photodynamic therapy in cancer. Therefore, repurposing clinically approved P&A might be an alternative to treat COVID-19. In this work, we evaluate the ability of the clinically approved temoporfin, verteporfin, talaporfin and redaporfin to inactivate SARS-CoV-2 infectious particles, characterizing their mechanism of action. Loss of infectivity of P&A treated SARS-CoV-2 was assessed by plaque assay. P&A photoactivation successfully inactivated SARS-CoV-2 with very low concentrations and light doses. However, only temoporfin and verteporfin were able to inactivate SARS-CoV-2 in the dark, verteporfin being the most effective. Next, P&A dark antiviral mechanism was characterized starting from P&A interaction with membrane models. P&A partition, membrane-insertion depth, lipid-membrane disruption and changes in membrane ordering were investigated using fluorescent spectroscopy. Among all tested P&A, verteporfin presented the highest partition coefficient, Kp. Curiously, temoporfin and redaporfin presented similar Kp values, although redaporfin did not present dark antiviral activity. Noteworthy, redaporfin was located closer to the surface of the lipid bilayer and both temoporfin and verteporfin were located closer to the centre. Finally, only temoporfin and verteporfin induced reduction of GP (laurdan-generalized polarization), with transition from an ordered phase to a liquidcrystalline phase. Our results suggest that dark antiviral activity is dependent on P&A interaction with viral envelope. Membrane affinity, penetration, and destabilization are critical for P&A dark antiviral activity. Furthermore, dark anti-SARS-CoV-2 activity opens the possibility for off-label P&A application in the systemic treatment of COVID-19.

Protoporphyrin IX and verteporfin potently inhibit SARS-CoV-2 infection in vitro and in a mouse model expressing human ACE2.

The SARS-CoV-2 infection is spreading rapidly worldwide. Efficacious antiviral therapeutics against SARS-CoV-2 is urgently needed. Here, we discovered that protoporphyrin IX (PpIX) and verteporfin, two Food and Drug Administration (FDA)-approved drugs, completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 µmol/L and 0.31 µmol/L, respectively, and their EC50 values of reduction of viral RNA were at nanomolar concentrations. The selectivity indices of PpIX and verteporfin were 952.74 and 368.93, respectively, suggesting a broad margin of safety. Importantly, PpIX and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human angiotensin-converting enzyme 2 (ACE2). The compounds, sharing a porphyrin ring structure, were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein. Our study suggests that PpIX and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.

Modeling the binding of protoporphyrin IX, verteporfin, and chlorin e6 to SARS-CoV-2 proteins.

In this work, we analyze the latest data on the molecular docking of a range of SARS-CoV-2 proteins to protoporphyrin IX, verteporfin, and chlorin e6, as well as consider the prospects for using chlorins and porphyrins as agents for photoinactivation of the SARS2 virus.