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Novel filovirus entry inhibitors based on a pseudo-symmetrical biphenyl core

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI118122-01
Agency Tracking Number: R41AI118122
Amount: $576,674.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: R
Solicitation Number: PA14-072
Solicitation Year: 2015
Award Year: 2015
Award Start Date (Proposal Award Date): 2015-03-01
Award End Date (Contract End Date): 2018-02-28
Small Business Information
Worcester, MA 01605-4307
United States
DUNS: 158864715
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (312) 355-0203
Business Contact
Phone: (508) 757-2800
Research Institution
CHICAGO, IL 60612-7224
United States

 Nonprofit College or University

DESCRIPTION provided by applicant Ebola EBOV and Marburg MARV viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of days Because of the safety concerns these viruses are designated as biosafety level agents Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans Although several promising vaccine candidates have been shown to be effective in eliciting host immune responses and to protect primates against viral infection the minimal time required for vaccination at least one month and the sporadic nature of outbreaks reinforce the urgent need to develop potent small molecule inhibitors against filoviral infections Thus it is imperative to
identify and develop potent inhibitors against filoviral infection These inhibitors are considered
to be of paramount importance for use during filoviral outbreaks or bioterrorist attacks This application defines a plan to develop potent small molecule inhibitors which block entry of EBOV and MARV into host cells Entry of EBOV and MARV is mediated by a single viral glycoprotein GP which is considered one of the major therapeutic targets GP consists of two subunits GP and GP GP is responsible for receptor binding and host tropism while GP mediates viral cell membrane fusion and viral entry We have used an HTS protocol targeting GP mediated viral entry to screen a small molecule library and we have identified compounds that inhibit entry of infectious EBOV MARV IC values M These hit compounds exhibit selectivity for EBOV MARV entry The overall objective of this Phase I application is to develop these inhibitors as potential anti filoviral therapeutics This application will focus on the folloing three specific aims Synthesize structurally diverse analogs of the anti Ebola SB hit series based on structure activity relationships SARs to improve potency and selectivity Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action MOA of the EBOV MARV inhibitors Select EBOV MARV inhibitors with in vitro ADME properties suitable for i v and oral dosing PUBLIC HEALTH RELEVANCE This project is to discover and develop small molecule entry inhibitors for Ebola and Marburg 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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