Introduction

Seasonal influenza and pandemic outbreaks typically result in high mortality and morbidity associated with severe economic burdens. Vaccines and anti-influenza drugs have made great contributions to control the infection. However, antigenic drifts and shifts allow influenza viruses to easily escape immune neutralization and antiviral drug activity. Hemagglutinin (HA)is an important envelope protein for the entry of influenza viruses into host cells, thus, HA-targeted agents may be potential anti-influenza drugs. Areas covered: In this review, we describe arbidol, a unique licensed drug targeting HA; discuss and summarize HA-targeted anti-influenza agents been tested before or being tested currently in clinical trials, including monoclonal antibodies, small molecule inhibitors, proteins and peptides. Other small molecule inhibitors are also briefly introduced. Expert opinion: Exploring new clinical applications for existing drugs can provide additional anti-influenza candidates with promising safety and bioavailability, and largely shortened time and costs. To enhance therapeutic efficacy and avoid drug-resistance, combination therapy involving in HA-targeted anti-influenza agent is reasonable and attractive. For drug discovery, it is helpful to keep an eye on the development of methodology in organic synthesis and probe into the co-crystal structure of HA in complex with small molecule.