Ebola (EBOV) and Marburg (MARV) viruses belong to the Filoviridae family and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction after an incubation period of 4-14 days. Due to safety concerns, these viruses are designated as biosafety level 4 agents. Currently, there is no effective vaccine or therapeutic treatment for filoviral infections in humans. Africa has recently (2014-2016) suffered a lethal EBOV epidemic with 27,000 people infected and more than11,000 deaths, underscoring the urgency of antiviral drug discovery and development. This Phase II application proposes to develop potent, small molecule inhibitors, which block entry of EBOV. We have identified compounds that inhibit entry of infectious EBOV/MARV with IC50 values in the nanomolar range. In Phase I, we synthesized structurally diverse analogs of the anti-Ebola CBS1118 hit series based on structure-activity relationships (SARs), to improve potency and selectivity. Prioritized inhibitors were validated in the infectious assay. We investigated the mechanism of action (MOA) of selected candidates, and identified druglike EBOV inhibitors with good in vitro ADME properties. In addition, these inhibitors display excellent pharmacokinetic parameters in mouse studies, following oral administration. In this application, we propose to accomplish the following three specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of the advanced lead compounds with EBOV glycoproteins; and (3) evaluate the in vivo efficacy and pharmacokinetics/toxicokinetics of the advanced lead compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
Project #
2R42AI126971-03A1
Application #
9845822
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Davis, Mindy I
Project Start
2016-08-07
Project End
2022-07-31
Budget Start
2019-08-16
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Chicago Biosolutions, Inc.
Department
Type
DUNS #
079936940
City
Chicago
State
IL
Country
United States
Zip Code
60612