Broad-spectrum antiviral activity of two structurally analogous CYP3A inhibitors against pathogenic human coronaviruses in vitro

The study titled “Broad-spectrum antiviral activity of two structurally analogous CYP3A inhibitors against pathogenic human coronaviruses in vitro” focuses on the antiviral properties of two drugs, cobicistat and ritonavir, against human coronaviruses, particularly SARS-CoV-2 and its variants.

Here’s a detailed summary:

Background: Coronaviruses like SARS-CoV, MERS-CoV, and SARS-CoV-2 pose a significant risk of outbreaks. The pandemic highlighted the need for effective antivirals. Cobicistat and ritonavir, both CYP3A inhibitors, have shown antiviral activity against early circulating SARS-CoV-2 strains. The study aims to compare their effects on various SARS-CoV-2 variants and other human coronaviruses​​​​.

Antiviral Activity against SARS-CoV-2 Variants: The study analyzed the effect of cobicistat and ritonavir on eight SARS-CoV-2 variants, including Alpha, Beta, Delta, Gamma, and Omicron subvariants. Using Vero E6 cells expressing TMPRSS2, which are highly susceptible to SARS-CoV-2, the drugs were tested at concentrations ranging from 1.25 to 20 μM. The study found that both drugs displayed antiviral activity at low micromolar concentrations, but cobicistat was consistently more potent than ritonavir. This was evidenced by lower EC50 values for cobicistat across all tested variants. The study showed that cobicistat is more effective than ritonavir in suppressing viral replication, especially when used in combination with nirmatrelvir, an Mpro inhibitor​​.

Combination with Nirmatrelvir: The antiviral effects of cobicistat and ritonavir were enhanced when combined with nirmatrelvir. This combination significantly increased antiviral effects for all SARS-CoV-2 VOCs and VOIs tested. Using the SynergyFinder plus tool, the study found that both combinations showed similar pan-variant synergism, with cobicistat/nirmatrelvir combination showing a significantly higher combination sensitivity score, suggesting a more profound suppression of viral replication​​.

Activity Against Other Coronaviruses: The study also tested the antiviral effects of cobicistat and ritonavir on other human coronaviruses, including the mildly pathogenic HCoV-229E and the highly pathogenic MERS-CoV. Both drugs were effective in inhibiting these viruses at low micromolar levels, with cobicistat showing higher potency. The addition of nirmatrelvir did not lead to a synergistic effect on HCoV-229E, suggesting the higher potency of cobicistat alone on this virus, but it did show synergistic effects against MERS-CoV when combined with either cobicistat or ritonavir​​.

Mechanism of Action and Clinical Implications: The study discusses the unclear mechanism of action for the antiviral activity of cobicistat and ritonavir. While both drugs are structurally similar, cobicistat has a higher potency, possibly due to the morpholine moieties in its structure. The study suggests that these drugs might inhibit viral entry through effects on the S protein and potentially alter lipid metabolism, affecting viral fusion and entry. The study highlights that leveraging the antiviral properties of these drugs would require higher dosing regimens than currently used in Paxlovid or HIV treatment. The study calls for further research to understand the mechanism behind the differing potencies of cobicistat and ritonavir and to evaluate the safety and feasibility of higher dosing in humans​​.

In summary, this study demonstrates that cobicistat, and to a lesser extent ritonavir, can be repurposed as effective antiviral agents against SARS-CoV-2 and other human coronaviruses. It suggests the potential for adjusting dosing regimens to maximize their antiviral properties.

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