The potential of devasting pandemic influenza outbreaks has
attracted a great amount of resources and efforts in the search for
possible prevention and effective treatment methods of influenza A
infections. Currently, two main strategies against the virus are
available, which are vaccination and small molecule anti-influenza
drugs. Anti-influenza small molecule drugs present the first line of
protection against the virus during an epidemic outbreak, especially
in the early stages, as an effective vaccine usually takes at least 6
months to develop for the circulating strains. Furthermore, vaccina-
tion has limited effectiveness in treatment of immunocompromised
patients. Moreover, anti-influenza drugs have demonstrated benefit
in clinical practices in terms of shortening the disease duration and
reducing the risk of influenza-caused serious complications and
death if patients are treated in a timely fashion. For all of these
reasons, anti-influenza drugs are necessary for the control of
influenza A virus pandemics. Currently, two major classes of drugs
are approved by FDA for anti-influenza A virus treatment:
admantane-based M2 ion channel protein blockers (amantadine
and rimantadine) and neuraminidase inhibitors (oseltamivir, zana-
mivir, and peramivir). However, the continuous evolvement of
influenza A virus and the rapid emergence of resistance to current
drugs, particularly to admantanes2 and oseltamivir3,4
, has raised
great concern for a possible pandemic flu, highlighting an urgent
need for developing new anti-influenza drugs against resistant
influenza A virus. In this review, we discuss recent progress made
in small-molecule drug development to overcome influenza A virus
resistance with a focus on novel drug design strategies targeting the
mutant M2 ion channel proteins and neuraminidases, as well as
other viral proteins not associated with current drugs.