Emerging host-targeted antivirals for respiratory viruses: antivirals targeting virus elements versus host mechanisms

• Traditional antiviral drug research has focused on direct-acting antivirals (DAAs). • DAAs have limitations such as narrow-spectrum activities and drug resistance. • Host-targeted antivirals (HTAs) can overcome the limitations of DAAs. • HTAs may have a risk for toxicity but a high barrier to drug resistance. • Combination therapy of DAAs and HTAs is critical to prepare for the next pandemic. Antivirals can be directed against the virus or host. Traditional antiviral drug discovery activities favor virus-targeting and virus-specific drugs. This strategy typically involves one viral target that is easy to design antiviral compounds to. These virus-specific direct-acting antivirals (DAAs) have relatively good toxicity profiles compared with those obtained from other strategies. To date, most approved antivirals are classified as DAAs. They target viral enzymes or structural proteins that are essential for viral replication. These traditional antivirals have been successfully used in clinical settings for years. However, virus-targeting DAAs have limitations. Resistance to almost all DAAs has been reported since viruses constantly mutate. Broad-spectrum DAAs face challenges in designing broadly acting compounds due to the differences in viral target structures and behaviors in host cells. Contrastingly, host-targeted antivirals (HTAs) can overcome drug resistance and exhibit broad-spectrum antiviral activity although they are associated with a comparatively elevated risk of toxicity. Considering the recent viral outbreaks, a large unmet need exists for the development of broad-spectrum antivirals with a high barrier to drug resistance, especially in the field of respiratory infections. It is critical to explore combination therapy with HTAs and DAAs that compensates for each other’s shortcomings. Combination regimens can cover a wider range of viruses and lead to a reduction in toxicity. In this review, we outline historical achievements and recent advances in the development of DAAs. We then discuss how the latest HTAs could provide valuable insights into fighting viral threats, focusing primarily on respiratory viruses.