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Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R42AI155039-01A1
Agency Tracking Number: R42AI155039
Amount: $300,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA20-265
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-04-02
Award End Date (Contract End Date): 2022-03-31
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, and have 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 six months to develop. Furthermore, vaccination has limited
effectiveness in the 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 neuraminidase
inhibitors (NAIs; oseltamivir, zanamivir and peramivir), while the influenza M2 ion channel blockers
(amantadine and rimantadine) are not now recommended since all of the circulating influenza strains
have acquired resistance. (Xofluza, a polymerase acidic endonuclease inhibitor, has just been approved
in 2018 and is yet untried during a flu season.) The rapid emergence of the NAI-resistant strains of
influenza A viruses strongly suggests that NAIs alone may not be sufficient as effective 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, with IC50 values in the
nanomolar range. We have synthesized structurally diverse analogs of the anti-influenza hit series using
structure-activity relationships (SARs) to improve potency and selectivity; validated the lead inhibitor
candidates in the infectious assay and investigated the mechanism of action (MOA) of the these
inhibitors; and selected anti-influenza inhibitors with excellent in vitro potency and selectivity values and
druglike in vivo pharmacokinetic properties. In this Fast Track STTR Phase I andamp;II application, we propose
four specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the
mechanism of action (MOA) of the advanced lead compounds with HA proteins; (3) evaluate the
pharmacokinetics/toxicokinetics of the advanced lead compounds; and (4) preclinical development.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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