Dimandelic Acid Ethers As Topical Microbicides For HIV

  • Herold, Betsy (PI)
  • Waller, Donald (PI)
  • Zaneveld, Lourens J. (PI)
  • Cara, Andrea (PI)
  • Klotman, Mary E. (PI)
  • Zaneveld, Lourens J. (PI)
  • Klotman, Mary E. (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): There are 16,000 new cases of HIV
infection everyday with over 36.1 million people living with HIV/AIDS today.
Worldwide, the vast majority of new infections with HIV are acquired through
sexual transmission, the major route of transmission to the 16.4 million
infected women. Compounds that are developed for topical use to prevent HIV
transmission (microbicides) offer a promising and perhaps more easily realized
alternative to development of an effective vaccine. However, recent
disappointing experience with a widely used contraceptive, nonoxynol-9,
emphasizes the need for extensive preclinical evaluation of compounds for
antiviral efficacy and toxicity prior to their widespread use as a topical
microbicide. This Program Project Grant will focus on the development of a
novel class of candidate compounds based on the parent compound, sodium
dimandelic acid ether (SAMMA). SAMMA has antiviral activity against
laboratory-adapted and primary isolates of HIVas well as herpes simplex virus
(HSV), the sexually transmitted disease that is a major cofactor for HIV,
without apparent cytotoxicity. It inhibits sperm function and prevents
fertilization in the rabbit.
Through the rational design of compound derivatives synthesized by a core
laboratory, critical structure/function relationships will be determined for
this class of compounds in studies designed to define the full HIV (Projects 1
and 3) and HSV (Projects 2 and 3) inhibitory spectrum, cytotoxicity (Projects
1,2,3 and 4), mechanism(s) of inhibition (Projects 1 and 2) and contraceptive
potential (Project 4). Mechanism studies will extend preliminary observations
that the parent compound works at an early step in viral entry for both HIV
and HSV by carefully studying viral and viral glycoprotein interactions with
cell membrane ligands involved in attachment and entry (Projects 1 and 2).
Initial cell interactions will be examined by using primary epithelial cells,
T -cells, macrophages and dendritic cells. To more closely simulate the
anatomical, physiologic and immunological environment of the genital mucosa,
Project 3 will examine the efficacy in cervical lavage and seminal fluid as
well as efficacy in human mucosal explant cultures and in a murine model of
HSV. Lastly, through co-culture of HIV and HSV in primary cells and in the
cervical mucosal explant culture, the added benefit of targeting both viruses
with topical microbicides will be defined. The proposed comprehensive
evaluation of this class of compounds will determine if it should progress to
clinical evaluation.
StatusFinished
Effective start/end date9/26/017/31/02

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development

ASJC

  • Drug Discovery
  • Microbiology (medical)
  • Analytical Chemistry
  • Infectious Diseases
  • Medical Laboratory Technology
  • Biochemistry
  • Virology
  • Immunology and Allergy
  • Toxicology
  • Pharmacology
  • Reproductive Medicine
  • Immunology
  • Organic Chemistry
  • Pharmaceutical Science

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