Developing a New Therapeutic for the Treatment of Invasive Aspergillosis

Information

  • Research Project
  • 8703007
  • ApplicationId
    8703007
  • Core Project Number
    R43AI106235
  • Full Project Number
    5R43AI106235-02
  • Serial Number
    106235
  • FOA Number
    PA-12-088
  • Sub Project Id
  • Project Start Date
    7/18/2013 - 11 years ago
  • Project End Date
    6/30/2015 - 9 years ago
  • Program Officer Name
    FRANCESCHI, FRANCOIS J
  • Budget Start Date
    7/1/2014 - 10 years ago
  • Budget End Date
    6/30/2015 - 9 years ago
  • Fiscal Year
    2014
  • Support Year
    02
  • Suffix
  • Award Notice Date
    6/2/2014 - 10 years ago

Developing a New Therapeutic for the Treatment of Invasive Aspergillosis

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA), caused by the fungus Aspergillus fumigatus, is associated with mortality rates of 40- 50%. In response to the lack of effective treatments, the Infectious Diseases Society of America highlighted A. fumigatus as one of only six pathogens for which it mandated that a substantive breakthrough is urgently needed. IA accounts for the largest financial burden of all invasive fungal infections, with an annual economic cost in the United States of over $1.1 billion. Driven by the growing immunosuppressed patient population, both the incidence and mortality due to A. fumigatus have risen three-fold in the last decade. While much is known regarding the cellular processes required for fungal pathogenesis, translating understanding into tangible clinical benefit has been difficult due to the fact that these fungal pathogens and their hosts have similar physiology. As a result, current antifungal agents have limited clinical efficacy, are poorly fungicidal in the host, are occasionally toxic, and are increasingly ineffective due to emerging resistance. Thus, innovative antifungal targeting agents and strategies are critically needed. It has been well established that molecules targeting fungal calcineurin (FC) have extremely potent antifungal activity against a broad range of fungi. Over the past decade, our collaborator has established that calcineurin is required for A. fumigatus hyphal growth and virulence. Moreover, calcineurin is required for fungal stress response and small molecule or genetic inhibition of calcineurin thwarts drug resistance. The challenge of exploiting FC as an antifungal agent is due to structural and sequence homology with human calcineurin (HC). Knowledge of the HC pathway and the immunosuppressive capacity of calcineurin inhibition has been one of the greatest contributions to our current solid organ and bone marrow transplantation abilities. However, inhibition of HC causes severe immunosuppression and toxicity. Recent chemical innovations have enabled Amplyx to rapidly create libraries of analogues of FK506 and FK520 that were previously synthetically intractable. These new chemistries have resulted in promising analogs with substantially lower immunosuppression than the parent compounds yet maintain a high-degree of antifungal activity. Based on these preliminary results, our goals in this proposal are to (1) Use existing structural data and perform computational modeling to design non-immunosuppressive calcineurin inhibitors of A. fumigatus; (2) Synthesize and purify a library of these calcineurin inhibitors for initial testing; and (3) Screen and select these compounds for low immunosuppression, potent antifungal activity, and favorable pharmacokinetics. The impact of this work will be to utilize a structural biologic approach to design, synthesize, and test fungal-specific calcineurin inhibitors with minimal immunosuppressive action and robust antifungal activity against both A. fumigatus wild-type and antifungal resistant strains, potentially transforming the treatment paradigm for IA.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R43
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    299119
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:299119\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    AMPLYX PHARMACEUTICALS, INC.
  • Organization Department
  • Organization DUNS
    780230004
  • Organization City
    SAN DIEGO
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    92121
  • Organization District
    UNITED STATES