PDE12 Enzyme Inhibition Promotes an Antiviral Response against Several RNA Viruses

Antiviral response by a host organism requires the activation of several effector pathways. These pathways need tight regulation provided by the enzyme phosphodiesterase 12 (PDE12). The enzyme functions to rapidly hydrolyze the effector pathway and terminate in Ribonuclease L (RNAseL). Effective innate immune responses against a wide range of human and animal viruses require activation of the effector pathway. Several gene studies have shown the reaction pathway determines the outcome for multiple infections such as Hepatitis C virus and Covid-19 disease recently. A new study proposed an inhibition of PDE12 to manipulate the activities of RNAseL as a therapeutic means to inhibit viral replication.

How SARS-Cov-2 Enters Cells

How SARS-Cov-2 Enters Cells

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PDE12 inhibition possesses antiviral activity in-vitro against clinically significant RNA viruses

Previous studies have shown reduced viremia and mortality rates in dengue virus-infected mice. The present study aimed to determine the impact of the enzyme PDE12 on antiviral pathways. The present research result shows that PDE12 can be inhibited by small molecules, which cause an increase in the cytoplasmic activity of RNAseL. This effector pathway is vital in reducing or preventing viral replication against an increased range of RNA viruses.

While tight regulation of RNAseL activity is required to avoid cell damage, targeting PDE12 has the advantage of requiring activation by dsRNA, providing specificity for virus-infected cells. PDE12 homozygous deletion causes embryonic lethality. In contrast, heterozygous deletion does not affect development, and animals are phenotypically normal.

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Higher levels of the antiviral pathway activity are present in rapidly proliferating cells, which may explain the effects in early development and may increase the risk of bone marrow or gastrointestinal side effects if PDE12 inhibition is used for an extended period. However, no abnormalities in hematological indices, bone marrow histology, or gastrointestinal effects occurred in the rodent toxicity experiments conducted before the in-vivo antiviral experiments.

The study shows a broad potential for PDE12 inhibition deployed as an antiviral. However, the effector pathway is ubiquitous across different organisms, and numerous viruses are developing strategies to resist RNAseL activity.

Clinical significance

Several antiviral medications are currently in use. These antiviral drugs with direct action have high potency and specificity. The antiviral drugs’ specific nature ensures that they are less likely to cause side effects. However, the emergence of drug-resistant viruses is a constant threat. The PDE12-inhibited pathway’s mechanism of action allows for fewer viral sequence differences, which may result in resistance. As seen in Covid, the enzyme approach is effective against a wide range of viral infections. Although, there is still a possibility of viral resistance even with the enzyme inhibition approach.

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Conclusion

Viral infections can be fatal in some cases. The discovery of better systemic means to serve as antiviral is vital in medicine. The inhibition of the PDE12 enzyme allows for a better chance of pathway activation against viral resistance. The discovery of the new approach can improve therapy against an array of viral infections.

References

Inhibition of Phosphodiesterase 12 results in Antiviral Activity against several RNA Viruses including SARS-CoV-2

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