Novel Therapeutics for Neurotropic Alphaviruses

Summary

Principal Investigator: David J Miller
Abstract: DESCRIPTION (provided by applicant): Neurotropic alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses are transmitted by mosquitoes, cause serious and potentially fatal central nervous system infections in humans, and are considered NIAID Category B Priority Pathogens due to their potential misuse as bioterrorism agents. Although vaccine development is in progress for several alphaviruses, there is an urgent and pressing need for broadly active antiviral agents against these virulent pathogens. Studies with experimental alphavirus encephalitis in mice have shown that while neurons are damaged directly by virus, uninfected neurons are also damaged via bystander mechanisms that involve altered homeostatic and neuroprotective functions of microglial cells or astrocytes. Thus, we hypothesize that combination therapy that directly targets virus replication and enhances neuroprotective responses will provide synergistic benefit in viral encephalitis. To identify and develop new antivirals to test this hypothesis, we recently screened a chemically defined small molecule library and identified a thieno[3,2-b]pyrrole compound that has potent activity against neurotropic alphaviruses in culture. Furthermore, a limited structure-activity relationship analysis with twenty structurally related analogs identified six additional compounds with enhanced in vitro activity. In addition, to explore the innovative use of natural products as a source for novel antivirals, we analyzed a series of extracts derived from marine actinomycetes and identified several that contained potent activity against alphaviruses. We are currently positioned to rapidly and efficiently move candidate antivirals through preclinical development, and we have assembled a team of experienced investigators with diverse expertise in the fields of virology, neurology, pathology, physiology, and medicinal chemistry to accomplish this task. The long-term goals of this highly collaborative project are to develop effective and broadly active therapies for encephalitis caused by neurotropic alphaviruses and related arboviruses. The specific aims of this proposal are: (1) targeted chemical modification of lead antiviral compounds, based on the initial structure-activity relationship analysis, to enhance potency, reduce toxicity, improve solubility and metabolic stability, and optimize membrane permeability;(2) identify molecular target(s) responsible for their antiviral activity;(3) analyze the in vivo pharmacokinetics and efficacy of candidate antivirals, including combination treatment with neuroprotective agents;and (4) isolate and characterize novel compounds with antiviral activity derived from marine microbes.
Funding Period: 2010-07-01 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Novel inhibitors of neurotropic alphavirus replication that improve host survival in a mouse model of acute viral encephalitis
    Janice A Sindac
    Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Med Chem 55:3535-45. 2012
  2. pmc Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication
    Janice A Sindac
    Vahlteich Medicinal Chemistry Core and Department of Medicinal Chemistry, College of Pharmacy, Departments of Internal Medicine and Microbiology and Immunology, Department of Neurology, Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109, United States
    J Med Chem 56:9222-41. 2013

Detail Information

Publications2

  1. pmc Novel inhibitors of neurotropic alphavirus replication that improve host survival in a mouse model of acute viral encephalitis
    Janice A Sindac
    Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Med Chem 55:3535-45. 2012
    ..These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses...
  2. pmc Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication
    Janice A Sindac
    Vahlteich Medicinal Chemistry Core and Department of Medicinal Chemistry, College of Pharmacy, Departments of Internal Medicine and Microbiology and Immunology, Department of Neurology, Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109, United States
    J Med Chem 56:9222-41. 2013
    ..In a preliminary mouse PK study, we were able to demonstrate that two new analogues could achieve higher and/or longer plasma drug exposures than our previous lead and that one compound achieved measurable drug levels in the brain. ..

Research Grants30

  1. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  2. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  3. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  4. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  5. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  6. Discovery and evaluation of anti-filovirus therapeutics targeting NPC1
    Kartik Chandran; Fiscal Year: 2013
    ..Chemically optimize validated hits for antiviral activity and in vitro pharmacology 5. Establish pharmacologic and toxicological profiles of lead inhibitors and evaluate them for antiviral efficacy in murine infection models ..
  7. Genome wide siRNA screen for identifying host factors required for ZAP function
    Margaret R Macdonald; Fiscal Year: 2013
    ..Ultimately, ideas for new approaches to treatment may be stimulated by this work, which may help prevent the devastating diseases caused by these viruses. ..
  8. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  9. Middle Atlantic Regional Center for Excellence for Biodefense and Emerging Infect
    MYRON MAX LEVINE; Fiscal Year: 2013
    ..abstract_text> ..
  10. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  11. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  12. Discovery and development of broad spectrum anti-flaviviral drugs
    Timothy A Haystead; Fiscal Year: 2013
    ..At this time there is little that can be done to prevent or treat the majority of flaviviral infections and therefore development of broad-spectrum anti-flaviviral drugs is of crucial importance. ..
  13. Targeting host deubiquitinases for broad spectrum anti-infective therapy
    Christiane Wobus; Fiscal Year: 2013
    ..This application proposes to develop broad-spectrum anti-infective therapeutics that have efficacy against many pathogens including multiple category B agents. ..