Development of group 2 influenza A virus entry inhibitors

Influenza A viruses belong to the Orthomyxoviridae family with a negative-sense,
segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity
and significant mortality. Vaccination is the most prevalent prophylactic means for
controlling influenza infections. However, an effective vaccine usually takes at least 6
months to develop for the circulating strains. Furthermore, vaccination has limited
effectiveness in treatment of immunocompromised patients, and its effectiveness is also
limited during a pandemic. The current therapeutic options for flu infections are all based
on the NA inhibitors (NAIs), while the influenza M2 ion channel blockers (amantadine
and rimantadine) are not recommended anymore since all the circulating influenza
strains are resistant to them. However, the rapid emergence of the NAI-resistant strains
of influenza A viruses strongly suggests that NAIs alone may not be sufficient as an
effective means of the anti-flu therapies, and thus new treatment options targeting the
other viral/host factors are urgently needed. This application defines a plan to develop
potent, small molecule inhibitors, which block entry of influenza A viruses. We have
identified compounds that inhibit entry of infectious influenza A viruses (IC50 values ≤1
µM). These hit compounds exhibit selectivity for H3N2 and H7N1 entry. The overall
objective of this Phase I application is to develop these inhibitors as potential anti-flu
therapeutics. This application will focus on the following three specific aims: (1)
Synthesize structurally diverse analogs of the anti-flu CBS1193 hit series based on
structure-activity relationships (SARs) to improve potency and selectivity. (2)
Validateothe lead inhibitor candidates in the infectious assay and investigate the
mechanism of action (MOA) of the inhibitors. (3) Select flu inhibitors with in vitro ADME
properties suitable for i.v. and oral dosing.Project Narrative
This project is to discover and develop small molecule entry inhibitors for influenza viral
infection. The proposed research will help to develop potential antiviral therapeutics.