Medicinal Chemistry Strategies for the Discovery of Antivirals Targeting to Influenza Virus PB2 Cap-binding Domain

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This review covers the strategies and challenges in the discovery and development of small-molecule inhibitors for the influenza A PB2 cap-binding domain.

Influenza is an acute respiratory infectious disease caused by influenza virus, leading to huge morbidity and mortality in humans worldwide. Despite the availability of antivirals in the clinic, the emergence of resistant strains calls for antivirals with novel mechanisms of action. The PB2 subunit of the influenza A virus polymerase is a promising target because of its vital role in the ‘cap-snatching’ mechanism. In this review, we summarize the technologies and medicinal chemistry strategies for hit identification, hit-to-lead and lead-to-candidate optimization, and current challenges in PB2 inhibitor development, as well as offering insights for the fight against drug resistance.

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