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Development of group 2 influenza A virus entry inhibitors

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI145727-01
Agency Tracking Number: R41AI145727
Amount: $599,998.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA18-575
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-04-01
Award End Date (Contract End Date): 2021-03-31
Small Business Information
Chicago, IL 60612-3515
United States
DUNS: 079936940
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (312) 355-0203
Business Contact
Phone: (630) 915-4575
Research Institution
CHICAGO, IL 60612-4305
United States

 Nonprofit College or University

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.

* Information listed above is at the time of submission. *

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